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Pexidartinib (formerly PLX-3397; CML-261; FP-113; trade name Turalio) is a multi-targeted, orally bioavailable RTK (receptor tyrosine kinase) inhibitor of Flt3, Kit, and CSF-1R that may have anticancer effects. Its IC50s are 20 nM, 10 nM, and 160 nM for CSF-1R, Kit, and Flt3, respectively, and they are inhibitory. The FDA approved Pexidartinib in August 2019 to treat giant-cell tumors of the tendon sheath (GC-TS). However, the Turalio Risk Evaluation and Mitigation Strategy (REMS) Program is the only way to access it in the United States.
Targets |
FGFR1 (IC50 = 10 nM); cFMS (IC50 = 20 nM); FLT3 (IC50 = 160 nM); KDR (IC50 = 350 nM); LCK (IC50 = 860 nM); FLT1 (IC50 = 880 nM); NTRK3 (IC50 = 890 nM)
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ln Vitro |
Pexidartinib (PLX-3397) is an ATP-competitive, potent, and selective inhibitor of CSF1R (cFMS) and c-Kit that exhibits selectivity for c-Kit and CSF1R over other related kinases, FLT3, KDR (VEGFR2), LCK, FLT1 (VEGFR1), and NTRK3 (TRKC), with IC50 values of 160, 350, 860, 880, and 890 nM, respectively.
CSF1R activity promote the growth of T-cell lymphomas in-vitro [5] Having established the expression and activation of CSF1R in TCL, we adopted a loss-of-function strategy to address its potential oncogenic role in these TCL using complementary molecular and pharmacologic approaches. We first used a clinically available and rationally designed tyrosine kinase inhibitor that is selective for CSF1R (Pexidartinib, PLX3397)(25,49). In order to confirm CSF1R inhibition upon pexidartinib treatment, TCL cells with autocrine-activation of CSF1R were treated with Pexidartinib. A marked decrease in CSF1R phosphorylation was observed upon treatment with pexidartinib (Figure 2A, supplementary figure 4A). Importantly, pexidartinib did not show any effect on the phosphorylation levels of the oncogenic kinase NPM-ALK which is expressed in a portion of the TCL cells evaluated (supplementary figure 4B). In addition, a dose-dependent decrease in proliferation was observed with exposure to pexidartinib (Figure 2B and supplementary figure 4D–E), however these effects were not observed in TCL cells that do not express CSF1R, supporting the relative selectivity of this FDA-approved agent (supplementary figure 4C). Consistent with these findings, treatment with pexidartinib was associated with increased apoptosis of TCL cells, as demonstrated by phosphatidylserine exposure (Figure 2C–E), PARP cleavage and Caspase 3 cleavage (Figure 2F and supplementary figure 4F). To further address the role of CSF1R in T-cell lymphoma growth, and exclude the possibility of off-target effects with a TKI, doxycycline-inducible stable expression of CSF1R-targeting shRNA were successfully generated in T-cell lymphoma-derived lines. Activation of CSF1R is associated with phosphorylation of different signaling pathways [5] Physiological engagement and activation of CSF1R results in downstream phosphorylation-dependent signaling that modifies the survival and differentiation of myeloid lineage cells(33,34). However, the downstream signals that are regulated by CSF1R activation in most non-myeloid lineage cells are not known. In order to characterize the signaling pathways that are activated by CSF1R, an unbiased phosphoproteomic approach was performed after inhibition of CSF1R activity with Pexidartinib in T-cell lymphoma lines. For this screening, Karpas 299 T-cell lymphoma lines were selected because the secretion of CSF1 ligand together with strong surface expression of CSF1R are present. This screen identified a total of 1936 independent phosphotyrosine peptides corresponding to 1123 proteins. In addition, a combined set of 8045 independent phophoserine/phosphothreonine peptides, corresponding to a total number of 3136 proteins were also identified in the screen (supplementary table 1 and 2). A significant reduction in CSF1R auto-phosphorylated peptides was observed in pexidartinib treated cells, further validating this approach (table 1, supplementary figure 5A and supplementary table 3). Hierarchical clustering was performed from three technical replicates, demonstrating that pexidartinib-treated cells formed a distinct cluster (Figure 4A and supplementary figure 5B), encompassing a total of 551 unique proteins with significant modifications in phosphorylated peptides. Out of those phosphorylated peptides, 451 were modifications in serine residues, 122 tyrosine residues and 113 threonine resides (supplementary table 3). Signaling pathway analysis of these changes following CSF1R inhibition was performed with Kyoto Encyclopedia of Genes and Genomes (KEGG online software), and was consistent with differential phosphorylation of PI3K/AKT-regulated signaling (Supplementary Table 1, Figure 4B). Also, modifications in proteins that participate in cellular processes, including metabolism, cell cycle progression and actin-cytoskeleton dynamics were also identified (Figure 4B, supplementary table 4 and supplementary figure 5C). To further explore the signaling pathways that are activated downstream of CSF1R signaling, an unbiased gene expression profile array was performed upon CSF1R inhibition with pexidartinib. The expression of 217 genes was significantly altered upon CSF1R inhibition with Pexidartinib (n=3, p<0.01; Figure 4C). Importantly, inhibition of CSF1R was associated with changes in the expression of genes that are involved in cytokine (JAK/STAT) signaling (Figure 4D). Similarly, the phosphoproteomic screening demonstrated differential phosphorylation of proteins that are involved in JAK/STAT signaling, including STAT1, STAT3, STAT5 and SOS2 (supplementary table 2). Because the T-cell line used in the screen harbors the oncogenic NPM-ALK fusion, cells treated with the ALK inhibitor crizotinib were included as a control. In comparison with ALK inhibition, 46% (n = 154 genes) of the changes in gene expression observed in pexidartinib-treated cells were specific for pexidartinib (Figure 4E), and expression of 63 genes were modified by treatment with either pexidartinib or crizotinib (Figure 4E). |
ln Vivo |
Pexidartinib (PLX3397; 0.25, 1 mg/kg, twice daily for 8 days) prevents the growth of BrdU-positive cells and microglia in neonatal mice[2].
Pexidartinib (1 mg/kg, twice daily for 8 day) does not appear to have any noticeable effects on mice's cleaved caspase-3-positive cells[2]. Pexidartinib (50 mg/kg; p.o.; every second day for 3 weeks) lowers tissue macrophage counts in mice without changing the homeostasis of glucose[4]. PLX3397 treatment substantially reduced macrophage numbers in adipose tissue of both chow and high-fat diet fed mice without affecting total myeloid cell levels. Despite this, PLX3397 did not greatly alter glucose homeostasis, did not affect high-fat diet-induced increases in visceral fat cytokine expression (Il-6 and Tnfa) and had limited effect on the phosphorylation of the stress kinases JNK and ERK and macrophage polarization.[4] Blockade of Chemotherapy-Induced TAM Recruitment [1] To determine whether tumor-infiltrating TAMs also regulate sensitivity of MECs to cytotoxic therapy, we blocked TAM infiltration in vivo with immunologic and pharmacologic agents (Supplementary Fig. S4) and evaluated myeloid cell infiltration of tumors from treated mice (Supplementary Fig. S5). Mice bearing orthotopic mammary tumors were treated with neutralizing monoclonal antibodies (mAb) CSF1 (clone 5S1) or CD11b (clone M1/70), or a competitive ATP inhibitor with potent (nM) specificity for CSF1 and cKIT receptor tyrosine kinases (Pexidartinib), either as a monotherapy or in combination with PTX. CD11b is an integrin cell adhesion molecule expressed on granulocytes, macrophages, monocytes, dendritic cells (DC), and natural killer cells that in part regulates transendothelial migration of cells into tissue and tumor parenchyma. PLX3397 has 10- to 100-fold selectivity for cKIT and CSF1R, as opposed to other related kinases, such as KDR (see Supplementary Fig. S6A and Methods; ref. 20). Fluorescence-activated cell sorting analysis of the predominant myeloid subtypes infiltrating mammary tumors revealed that either as monotherapy, or in combination with PTX, CD45+CD11b+Ly6C−Ly6G−F4/80+ TAM recruitment was significantly diminished following treatment with either αCSF1 mAb or Pexidartinib, with no effect on infiltration of CD45+CD11b+LY6Ghigh iMCs or CD45+CD11blow/−Ly6C−CD22−Ly6G−CD11chighMHCIIhigh DCs (Fig. 3A and B; Supplementary Fig. S5A and B). Treatment with aCD11b mAb decreased both TAM and iMC infiltration (Fig. 3A). Analysis of the maturation and differentiation status of TAMs remaining in mammary tumor tissue following αCSF1 or PLX3397 treatment revealed no significant change in CD11b, CD11c, F4/80, CD45, or MHCII expression (Supplementary Fig. S5B). However, examination of mammary tumor sections revealed a population of perivascular CSF1-independent F4/80+ TAMs remaining (Fig. 3C). Blockade of TAM recruitment was a direct effect of CSF1/CSF1R blockade: In vitro CSF1R inhibition efficiently blocked CD11b+ monocyte chemotaxis in response to control or PTX-treated pMEC–conditioned medium, with no effect on chemotaxis of CD3+ T lymphocytes (Fig. 3D; Supplementary Fig. S3G). These results were mirrored in vivo; treatment of late-stage MMTV-PyMT mice with PLX3397 significantly inhibited both steady-state and PTX-induced tumor infiltration by CD45+CD11b+Ly6C−Ly6G−F4/80+ TAMs (Fig. 3E; Supplementary Fig. S5) without altering TAM maturation/differentiation (Supplementary Fig. S6B). We next treated 80-day-old MMTV-PyMT mice, or mice bearing syngeneic orthotopic PyMT-derived tumors (~1.0 cm) with αCSF1, αCD11b, or Pexidartinib (vs controls) for 5 days, followed by 4 cycles of PTX (10 mg/kg, i.v.; Supplementary Fig. S4). Primary tumor burden at study endpoints (2.0 cm primary tumors or 100 days of age) was significantly reduced in mice treated with combined αCSF1/PTX, αCD11b/PTX, or PLX3397/PTX therapy, compared to mice treated with these as single agents (Fig. 4A and B; Supplementary Fig. S7A). Similar results were observed in syngeneic mice bearing orthotopic PyMT-derived mammary tumors receiving combined PLX3397/carboplatin (CBDCA) therapy (Fig. 4B). Mammary tumors in MMTV-PyMT mice progress through well-defined stages of cancer development, similar to progression of breast cancer in women, including tissue with florid ductal hyperplasia, ductal carcinoma in situ with early stromal invasion, and poorly differentiated invasive ductal carcinoma (15, 21). Using this staging criterion, we observed that mammary tumors arising in MMTV-PyMT mice treated with combined Pexidartinib/PTX therapy exhibited decreased development of late-stage carcinoma, compared with tumors in age-matched mice treated with either PTX or Pexidartinib as monotherapy (Fig. 4C; Supplementary Fig. S7B). Moreover, the late-stage carcinomas that did develop in PLX3397/PTX-treated mice contained large areas of necrosis (Supplementary Fig. S7C) characterized by increased presence of apoptotic cells, as measured by cleaved caspase 3-positivity (Fig. 4D) with no accompanying change in epithelial proliferation (Supplementary Fig. S7D). Decreased Vascular Density Accompanies Improved Chemosensitivity [1] It is known that TAMs provide VEGF to developing mammary tumors and thereby regulate angiogenic programming of tissue (22–24). Chemosensitivity to CDDP in MMTV-PyMT mice is in part regulated by myeloid-derived VEGF (25); thus, we sought to determine if TAM depletion altered VEGF expression and/or density of CD31+ vessels in MMTV-PyMT mice treated with PTX. Whereas total VEGF mRNA expression was significantly reduced by Pexidartinib (Fig. 4E), this 70% reduction did not correlate with a change in vascular density (Fig. 4F). In contrast, combined PLX3397/PTX therapy resulted in a significant reduction in CD31+ vessel density within mammary tumors, paralleling induction of apoptosis and necrosis (Fig. 4F). CSF1-Signaling Blockade Enhances Antitumor Immunity and CTL Infiltration in Response to Chemotherapy [1] Because analysis of human breast cancer tissues revealed that high stromal TAM density inversely correlated with CD8+ T-cell infiltration (Supplementary Table S1), we predicted that depletion of TAMs would enhance CD8+ CTL infiltration and thereby foster an antitumor immune microenvironment. Analyses of tumor-infiltrating T lymphocytes in mice treated with αCSF1/PTX or Pexidartinib/PTX by flow cytometry or IHC revealed significantly increased presence of CD4+ and CD8+ T cells in mammary tumors (Fig. 5A and B; Supplementary Fig. S8A). Consistent with these findings, cytokine mRNA expression in mammary tissue derived from PLX3397/PTX-treated MMTV-PyMT mice revealed increased mRNA expression of cytotoxic effector molecules, including IFN-γ, granzyme A, granzyme B, perforin-1, and the type 1 DC effector molecules IL12p35 and IFN-α (Fig. 5C). In contrast, expression of the immunosuppressive molecule arginase-1 was decreased by PLX3397/PTX therapy (Fig. 5C). This reprogramming of the immune microenvironment was accompanied by increased tumor infiltration of CD45+CD11blow/−CD19−Ly6G−Ly6ClowCD11chighMHCIIhigh DCs (Fig. 5D), indicating that combined treatment of MMTV-PyMT mice with PLX3397/PTX fostered an antitumor immune response by T lymphocytes expressing high levels of cytotoxic effector molecules. Macrophage Depletion Enhances Chemotherapeutic Response in a CD8∙ CTL-Dependent Manner [1] To determine whether increased chemosensitivity of mammary tumors in Pexidartinib/PTX-treated mice was dependent on enhanced CD8+ T-cell response, we depleted CD8+ T cells from late-stage MMTV-PyMT mice treated with PTX or PLX3397 or both. Findings from this study revealed that the improved outcome with enhanced chemosensitivity resulting from combined PLX3397/PTX therapy was indeed a CD8+ T-cell–dependent response (Fig. 6A and B; Supplementary Fig. S8B). We found that CD8 depletion also resulted in increased tumor grade and decreased presence of cleaved caspase-3–positive cells in mice that had received combined PLX3397/PTX therapy (Fig. 6C and D). Taken together, these data indicate that the enhanced cytotoxic response elicited by CSF1R-signaling blockade was CD8+ T-cell–dependent. Combined Macrophage Depletion and Chemotherapy Blocks Metastasis in a CD8-Dependent Manner [1] Long-term survival of breast cancer patients is often limited by disseminated metastases following surgical resection of primary tumors. Analysis of leukocyte profiles in human breast cancers demonstrated that OS, and thus presumably metastatic spread, were regulated by the spectrum of tumor-infiltrating T lymphocytes and macrophages present. In MMTV-PyMT mice, although neither CSF1R-signaling blockade nor PTX therapy alone inhibited development of pulmonary metastasis, mice receiving combined Pexidartinib/PTX exhibited >85% reduction in pulmonary metastases that was in part CD8+ T-cell–dependent (Fig. 6E). Pexidartinibtreatment of neonatal mice decreased the number of microglia and BrdU-positive proliferative cells [2] PLX3397, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, is generally used for microglial depletion. In this study, neonatal mice were treated with PLX3397 with an intraperitoneal injection (Figure 3A). The treatment with PLX3397 twice daily from P0 to P7 decreased the number of microglia (p=0.015, Figure 3B,C). PLX3397 also decreased the number of BrdU-positive proliferative cells in the retina at 500 μm from the optic nerve (p=0.021, Figure 3D,E). To determine that the proliferative cells were retinal precursor cells, we costained BrdU and the retinal precursor cell markers, Pax6 and Chx10, which is also known as visual system homeobox 2 (Vsx2). PLX3397 statistically significantly decreased the BrdU and Chx10 double-positive cells and tended to decrease BrdU and Pax6 double-positive cells (p=0.038, Figure 3F,G). PLX3397 did not alter the number of cleaved caspase-3-positive cells (Figure 3H). Pexidartinib/PLX3397 treatment substantially reduced macrophage numbers in adipose tissue of both chow and high-fat diet fed mice without affecting total myeloid cell levels. Despite this, PLX3397 did not greatly alter glucose homeostasis, did not affect high-fat diet-induced increases in visceral fat cytokine expression (Il-6 and Tnfa) and had limited effect on the phosphorylation of the stress kinases JNK and ERK and macrophage polarization. Conclusions: Our results indicate that macrophage infiltration of adipose tissue induced by a high-fat diet may not be the trigger for impairments in whole body glucose homeostasis, and that anti-CSF1 therapies are not likely to be useful as treatments for insulin resistance [4]. Activation of CSF1R promotes PTCL growth in-vivo [5] In order to further address the therapeutic relevance of these findings, the growth of T-cell lymphoma xenografts was evaluated upon CSF1R inhibition with Pexidartinib. Murine CSF1 does not bind human CSF1R(48,59); therefore, the autocrine-dependent CSF1R activation was evaluated in Karpas 299 xenografts generated in NSG mice. Tumor-bearing mice were treated with sham- or pexidartinib-containing chow, and no treatment-related toxicity was appreciated. An approximately 50% reduction in tumor growth was observed in pexidartinib-treated mice (n=24, p<0.05; Figure 6A and B), and increased apoptosis was observed from protein extracts of tumors treated with pexidartinib (Figure 6C). Phosphorylation of CSF1R (Y699) and p70S6K (T389) were examined as pharmacodynamic biomarkers using protein extracts from these xenografts, and a significant reduction in phosphorylation was observed in pexidartinib-treated mice (Figure 6D). In similarly designed experiments, SUP-M2 cells (that require exogenous CSF1) were utilized, and xenografts generated in immunodeficient mice that either transgenically express human CSF1(48) or in non-CSF1 expressing controls. An approximately 3-fold increase in tumor volume was observed in CSF1 producing mice compared with control mice (n=32, p<0.001; Figure 6E and F). Importantly, tumor growth was inhibited in pexidartinib-treated CSF1 transgenic mice (n=15, p<0.001; Figure 6E and F). However, no significant change in tumor growth was observed in the control mice treated with pexidartinib (Figure 6E and F). Overall, these findings demonstrate that activation of CSF1R, in either an autocrine- or paracrine-dependent manner, promotes T-cell lymphoma growth, and further supports CSF1R as a rational therapeutic target in these lymphomas (supplementary figure 7). |
Enzyme Assay |
Biochemical selectivity and potency of Pexidartinib (PLX3397): [1]
Pexidartinib (PLX3397) selectively inhibits the c-Fms and the c-Kit receptor tyrosine kinases, with biochemical IC50 values of 0.02 µM and 0.01 µM respectively (Figure S6A). Pexidartinib (PLX3397) was identified as a potent CSF-1R and c-KIT kinase inhibitor by using a Scaffold- and X-ray structure-based discovery approach. In a comprehensive screen of 226 different kinases, including representatives of all protein kinase subfamilies and several lipid kinases, Pexidartinib (PLX3397) at 0.03 µM and 1.0 µM only inhibited five other kinases significantly. Pexidartinib (PLX3397) was selected based on inhibition of the CSF1-dependent proliferation of the murine myelogenous leukemia cell line M-NFS-60, with an IC50 of 0.44 µM the murine macrophage cell line Bac1.2F5, with an IC50 of 0.22 µM. The human acute megakaryoblastic leukemia cell line M-07e, which depends on the addition of SCF for growth, was inhibited by Pexidartinib (PLX3397) with an IC50 of 0.1 µM. These sub-micromolar potencies confirm that Pexidartinib (PLX3397) can enter cells and inhibit Fms-driven cell growth.[1] Pexidartinib (PLX-3397) is an ATP-competitive, potent, and selective inhibitor of CSF1R (cFMS) and c-Kit that exhibits selectivity for c-Kit and CSF1R over other related kinases, FLT3, KDR (VEGFR2), LCK, FLT1 (VEGFR1), and NTRK3 (TRKC), with IC50 values of 160, 350, 860, 880, and 890 nM, respectively. |
Cell Assay |
CSF1R activity promote the growth of T-cell lymphomas in-vitro[5]
Having established the expression and activation of CSF1R in TCL, we adopted a loss-of-function strategy to address its potential oncogenic role in these TCL using complementary molecular and pharmacologic approaches. We first used a clinically available and rationally designed tyrosine kinase inhibitor that is selective for CSF1R (Pexidartinib, PLX3397). In order to confirm CSF1R inhibition upon pexidartinib treatment, TCL cells with autocrine-activation of CSF1R were treated with pexidartinib. A marked decrease in CSF1R phosphorylation was observed upon treatment with pexidartinib (Figure 2A, supplementary figure 4A). Importantly, pexidartinib did not show any effect on the phosphorylation levels of the oncogenic kinase NPM-ALK which is expressed in a portion of the TCL cells evaluated (supplementary figure 4B). In addition, a dose-dependent decrease in proliferation was observed with exposure to pexidartinib (Figure 2B and supplementary figure 4D–E), however these effects were not observed in TCL cells that do not express CSF1R, supporting the relative selectivity of this FDA-approved agent (supplementary figure 4C). Consistent with these findings, treatment with pexidartinib was associated with increased apoptosis of TCL cells, as demonstrated by phosphatidylserine exposure (Figure 2C–E), PARP cleavage and Caspase 3 cleavage[5]. PLX3397/Pexidartinib is found to be a strong inhibitor of both CSF-1R and c-KIT kinase through the application of scaffold- and X-ray structure-based discovery methodology. The SelectScreenTM profiling service provided the IC50 data. Leukocyte chemotaxis assay: For cell migration, PBLs were collected from peripheral blood of FVB/n mice following cardiac puncture, and seeded (105 cells/ 100 µl DMEM containing 0.1% BSA) onto the top chamber of transwell filters (3-µm). Filters were placed in a 24-well plate that contains conditioned medium isolated from vehicle or PTX (20 nM) pretreated MMTV-PyMT-derived MECs. For some conditions, Pexidartinib/PLX3397 (50 nM) was added to the upper chamber. 6-hr following incubation, the media in the lower chamber was isolated and analyzed by flow cytometry for CD11b, CD3 and 7AAD as described above. Samples were run in triplicates for each experimental group and experiments were repeated twice. [1] |
Animal Protocol |
MMTV-PyMT mice
40 mg/kg/day p.o. Two murine models of mammary tumor development were used to analyze response to chemotherapy (Supplementary Fig. S3). The first model used MMTV-PyMT mice (Supplementary Fig. S3A). The 80-day-old MMTV-PyMT female littermates were randomized by initial tumor volume and fed either PLX3397 formulated in mouse chow or control chow (provided by Plexxikon Inc). Pexidartinib/PLX3397 was formulated in mouse chow so that the average dose per animal per day was 40 mg/kg. When PLX3397-treated MMTV-PyMT mice reached 85 days of age, they were then administered PTX every 5 days by i.v. injection into the retroorbital plexus. PTX was given at 10 mg/kg of the animal per injection, diluted in PBS. Tumor burden was evaluated by caliper measurement every 5 days following the start of PLX3397 treatment. Prior to tissue collection, mice were cardiac-perfused with PBS to clear peripheral blood. Mammary tumor tissue from PBS-perfused MMTV-PyMT mice was analyzed by flow cytometry and qRT-PCR 2 days after the second dose of PTX, when metastatic burden and tumor grade were determined. Primary tumor burden was determined by caliper measurements on live sedated mice. Metastatic burden was assessed by serial sectioning of formalin-fixed paraffin-embedded lung tissue whereby the entire lung was sectioned and the number of metastatic foci (>5 cells) was determined on 6 sections taken every 100 µm following H&E staining. Lungs from >10 mice/group were analyzed[1]. A Ten-week-old mice were fed a chow or high-fat diet for 10 weeks and then treated with Pexidartinib/PLX3397 via oral gavage (50 mg/kg) every second day for 3 weeks, with subsequent monitoring of glucose tolerance, insulin sensitivity and assessment of adipose tissue immune cells.PLX3397 treatment substantially reduced macrophage numbers in adipose tissue of both chow and high-fat diet fed mice without affecting total myeloid cell levels. Despite this, PLX3397 did not greatly alter glucose homeostasis, did not affect high-fat diet-induced increases in visceral fat cytokine expression (Il-6 and Tnfa) and had limited effect on the phosphorylation of the stress kinases JNK and ERK and macrophage polarization.[4] Preclinical Mouse Models and Animal Husbandry [1] Mice harboring the PyMT transgene under the control of the MMTV promoter in the FVB/n strain were used. Two murine models of mammary tumor development were used to analyze response to chemotherapy (Supplementary Fig. S3). The first model used MMTV-PyMT mice (Supplementary Fig. S3A). The 80-day-old MMTV-PyMT female littermates were randomized by initial tumor volume and fed either Pexidartinib/PLX3397 formulated in mouse chow or control chow. PLX3397 was formulated in mouse chow so that the average dose per animal per day was 40 mg/kg. When PLX3397-treated MMTV-PyMT mice reached 85 days of age, they were then administered PTX every 5 days by i.v. injection into the retroorbital plexus. PTX was given at 10 mg/kg of the animal per injection, diluted in PBS. Tumor burden was evaluated by caliper measurement every 5 days following the start of PLX3397 treatment. Prior to tissue collection, mice were cardiac-perfused with PBS to clear peripheral blood. Mammary tumor tissue from PBS-perfused MMTV-PyMT mice was analyzed by flow cytometry and qRT-PCR 2 days after the second dose of PTX, when metastatic burden and tumor grade were determined. Primary tumor burden was determined by caliper measurements on live sedated mice. Metastatic burden was assessed by serial sectioning of formalin-fixed paraffin-embedded lung tissue whereby the entire lung was sectioned and the number of metastatic foci (>5 cells) was determined on 6 sections taken every 100 µm following H&E staining. Lungs from >10 mice/group were analyzed. To assess tumor grade, the stage characterization technique classified tumor tissue into 3 levels of histologic progression by quantifying the area of transformed glands occupied by each stage. Progression follows from a “precancerous stage” characterized by premalignant hyperplasia and adenoma/mouse intestinal epithelium but with the retention of some normal ductal and acinar mammary gland morphology, to a more epithelial cell–dense “early carcinoma” with some stromal invasion, and finally to an invasive, high–mitotic index “late-stage carcinoma.” The IHC analysis was conducted on tissue sections following the end of studies on 100-day-old MMTV-PyMT mice (detailed in Supplementary Fig. S4A). Vehicle-treated mice received PBS-only injections. We also used a syngeneic orthotopic implantable tumor model (referred to as PyMT-implantable in all figures and detailed in Supplementary Fig. S4B). For this model, single-cell suspensions of tumor cell pools isolated from mammary tumors of 3 or 4 100-day-old MMTV-PyMT mice were generated following collagenase A digestion (see discussion of flow cytometry analysis earlier). A total of 1.0 million tumor cells from pools were diluted in medium and basement membrane extract and injected orthotopically into uncleared mammary fat pads (4th gland) of 10-week-old virgin FVB/n female mice. Following implantation, tumors were allowed to grow to a mean diameter of 1.0 cm before enrollment into studies. Mice were randomized into treatment groups based on tumor size and treated with Pexidartinib/PLX3397 and PTX, as described above. For some studies, CBDCA was used and administered at 10 mg/kg of mouse per injection, in a similar manner to administration of PTX (see above). For mice with implantable tumors, tumor burden was evaluated by caliper measurement every 2 to 3 days following the start of PLX3397 treatment, and mammary tissue was analyzed by flow cytometry, IHC, and qRT-PCR at the end of the study (Supplementary Fig. S3B). Immune-depleted mice were injected i.p. every 5 days with either 1.0 mg anti-CD8 immunoglobulin G (YTS169.4) or isotype control rat immunoglobulin on day 1 followed by 500 µg every 5 days. PLX3397/Pexidartinib treatment [2] PLX3397 (Pexidartinib) was treated at a dose of 0.25 and 1 mg/kg (i.p., twice daily) to neonatal mice from P0 to P7. PLX3397 250 mg/ml in 100% dimethyl sulfoxide (DMSO) was prepared as the stock solution. The stock solution was diluted with PBS for the injected solution (0.25 mg/ml in PBS plus 0.1% DMSO). The control group was treated with an equal amount of 0.1% DMSO in PBS. BrdU was injected similarly as described above. At P7, the mice were euthanized, and the eyes were enucleated. Mice were housed under specific-pathogen free conditions. SUPM2 or Karpas 299 cells (2 × 106) were injected subcutaneously in immunodeficient NSG mice or Rag2/Il2rg immunodeficient mice with transgenic expression of humanized CSF1 ligand(48). Upon injections, mice were fed with either nutritionally complete pexidartinib-containing (275mg PLX3397/kg) or control chow, provided under MTA by Plexxikon. Toxicity secondary to drug delivery was assessed by daily monitoring of clinical condition (appearance, activity and body condition). Tumors were measured and mice humanely euthanized approximately 14 days after pexidartinib- or control-treatment. |
ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Following administration of single doses in healthy subjects and multiple doses in patients, the mean Cmax was 8625 ng/mL and the mean AUC was 77465 ngxh/mL. The median Tmax was 2.5 hours and the time to reach the steady state was approximately 7 days. Administration of pexidartinib with a high fat meal resulted in an increased drug Cmax and AUC by 100%, with a delay in Tmax by 2.5 hours. Pexidartinib is predominantly excreted via feces, where fecal excretion accounts for 65% of total pexidartinib elimination. Via this route of elimination, about 44% of the compound found in feces is recovered as unchanged parent drug. The renal elimination accounts for 27% of pexidartinib elimination, where more than 10% of the compound is found as the N-glucuronide metabolite. The apparent volume of distribution of pexidartinib is about 187 L. In rats, pexidartinib was shown to penetrate into the central nervous system. The apparent clearance is about 5.1 L/h. Metabolism / Metabolites Pexidartinib primarily undergoes oxidation mediated by hepatic CYP3A4 and glucuronidation by UGT1A4. Following UGT1A4-mediated glucuronidation, a major inactive N-glucuronide metabolite is formed with approximately 10% higher exposure than the parent drug after a single dose administration of pexidartinib. Based on the findings of _in vitro_ studies, CYP1A2 and CYP2C9 may also play a minor role in drug metabolism. Biological Half-Life The elimination half-life is about 26.6 hours. |
Toxicity/Toxicokinetics |
Hepatotoxicity
Elevations in serum aminotransferase levels are common during pexidartinib therapy, occurring in 50% to 90% of patients and rising above 5 times the upper limit of the normal range in 12% to 20%. In addition, elevations in alkaline phosphatase levels occur in up to 20% of treated persons. In registration trials, clinically apparent liver injury with jaundice developed in 5% of patients. The time to onset of liver injury was typically between 2 and 6 weeks, and the pattern of liver enzyme elevations was mixed or cholestatic. Autoimmune and immune-allergic features were not prominent. Liver biopsy demonstrated bile duct injury and loss, and at least 3 patients in studies for conditions other than TGCT developed bile duct paucity and features of vanishing bile duct syndrome that ultimately led to liver transplantation in one subject. Pexidartinib has had limited clinical use and the frequency and spectrum of acute liver injury with its use is not yet well defined. Likelihood score: B (likely cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of pexidartinib during breastfeeding. Because pexidartinib is over 99% bound to plasma proteins, the amount in milk is likely to be low. However, the manufacturer recommends that breastfeeding be discontinued during pexidartinib therapy and for 1 week after the last dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Based on the findings of _in vitro_ plasma protein binding study, pexidartinib is about 99% bound to serum proteins, where it is extensively bound to human serum albumin by 99.9% and alpha-1-acid glycoprotein by 89.9%. LiverTox Summary Pexidartinib is an orally available small molecule multi-kinase inhibitor that is used as an antineoplastic agent in the treatment of tenosynovial giant cell tumors. Pexidartinib is associated with a high rates of serum aminotransferase and alkaline phosphatase elevations during therapy and has been implicated in several cases of clinically apparent liver injury marked by progressive intrahepatic bile duct injury, some of which resulted in liver transplantation or were fatal. |
References |
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Additional Infomation |
Pharmacodynamics
Pexidartinib works by suppressing the growth of tenosynovial giant cell tumors. In clinical trials comprising of patients with symptomatic tenosynovial giant cell tumor, pexidartinib had a higher overall response rate, characterized by improved patient symptoms and functional outcomes, compared to placebo. Pexidartinib works by inhibiting the activation and signaling of tumor-permissive cytokines and receptor tyrosine kinases that play a central role in tumor cell proliferation and survival. Taking pexidartinib with a high-fat meal may increase the incidence and severity of adverse reactions, including hepatotoxicity. Pexidartinib is a pyrrolopyridine that is 5-chloro-1H-pyrrolo[2,3-b]pyridine which is substituted by a [6-({[6-(trifluoromethyl)pyridin-3-yl]methyl}amino)pyridin-3-yl]methyl group at position 3. It is a potent multi-targeted receptor tyrosine kinase inhibitor of CSF-1R, KIT, and FLT3 (IC50 of 20 nM, 10 nM and 160 nM, respectively). Approved by the FDA for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT). It has a role as an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor and an antineoplastic agent. It is a pyrrolopyridine, an organochlorine compound, an aminopyridine, an organofluorine compound and a secondary amino compound. Pexidartinib is a selective tyrosine kinase inhibitor that works by inhibiting the colony-stimulating factor (CSF1)/CSF1 receptor pathway. Pexidartinib was originally developed by Daiichi Sankyo, Inc. and it was approved by the FDA in August 2019 as the first systemic therapy for adult patients with symptomatic tenosynovial giant cell tumor. Tenosynovial giant cell tumor is a rare form of non-malignant tumor that causes the synovium and tendon sheaths to thicken and overgrow, leading to damage in surrounding joint tissue. Debilitating symptoms often follow with tenosynovial giant cell tumors, along with a risk of significant functional limitations and a reduced quality of life in patients. While surgical resection is a current standard of care for tenosynovial giant cell tumor, there are tumor types where surgeries are deemed clinically ineffective with a high risk of lifetime recurrence. Pexidartinib works by blocking the immune responses that are activated in tenosynovial giant cell tumors. In clinical trials, pexidartinib was shown to promote improvements in patient symptoms and functional outcomes in TGCT. Pexidartinib is available in oral formulations and it is commonly marketed as Turalio. Pexidartinib is a Kinase Inhibitor. The mechanism of action of pexidartinib is as a Kinase Inhibitor, and Tyrosine Kinase Inhibitor, and Colony Stimulating Factor Receptor Type 1 (CSF-1R) Inhibitor, and Cytochrome P450 3A Inducer, and Cytochrome P450 2B6 Inhibitor, and UGT1A1 Inhibitor. Pexidartinib is an orally available small molecule multi-kinase inhibitor that is used as an antineoplastic agent in the treatment of tenosynovial giant cell tumors. Pexidartinib is associated with a high rates of serum aminotransferase and alkaline phosphatase elevations during therapy and has been implicated in several cases of clinically apparent liver injury marked by progressive intrahepatic bile duct injury, some of which resulted in liver transplantation or were fatal. Pexidartinib is a small-molecule receptor tyrosine kinase (RTK) inhibitor of proto-oncogene receptor tyrosine kinase (KIT), colony-stimulating factor-1 receptor (CSF1R) and FMS-like tyrosine kinase 3 (FLT3), with antineoplastic activity. Upon oral administration, pexidartinib targets, binds to and inhibits phosphorylation of KIT, CSF1R and FLT3 harboring an internal tandem duplication (ITD) mutation. This results in the inhibition of tumor cell proliferation. FLT3, CSF1R and FLT3 are overexpressed or mutated in many cancer cell types and play major roles in tumor cell proliferation and metastasis. PEXIDARTINIB is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2019 and is indicated for neoplasm and tenosynovial giant cell tumor and has 16 investigational indications. This drug has a black box warning from the FDA. Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)-dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor-bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell-dependent manner. These data provide a rationale for targeting macrophage recruitment/response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach. Significance: These findings reveal that response to chemotherapy is in part regulated by the tumor immune microenvironment and that common cytotoxic drugs induce neoplastic cells to produce monocyte/macrophage recruitment factors, which in turn enhance macrophage infiltration into mammary adenocarcinomas. Blockade of pathways mediating macrophage recruitment, in combination with chemotherapy, significantly decreases primary tumor progression, reduces metastasis, and improves survival by CD8+ T-cell-dependent mechanisms, thus indicating that the immune microenvironment of tumors can be reprogrammed to instead foster antitumor immunity and improve response to cytotoxic therapy. [1] Purpose: In mice, retinal development continues throughout the postnatal stage accompanied by the proliferation of retinal precursor cells. Previous reports showed that during the postnatal stage microglia increase from postnatal day 0 (P0) to P7. However, how microglia are associated with retinal development remains unknown. Methods: The involvement of microglia in retinal development was investigated by two approaches, microglial activation and loss, using lipopolysaccharide (LPS) and PLX3397 (Pexidartinib), respectively. Results: LPS injection at 1 mg/kg, intraperitoneally (i.p.) in the neonatal mice increased the number of retinal microglia at P7. 5-Bromo-2´-deoxyuridine (BrdU)-positive proliferative cells were increased by LPS treatment compared to the control group. The proliferative cells were mainly colocalized with paired box 6 (Pax6), a marker of retinal precursor cells. However, the depletion of microglia by treatment with PLX3397 decreased the BrdU-positive proliferative cells. Moreover, progranulin deficiency decreased the number of microglia and retinal precursor cells. Conclusions: These findings indicated that microglia regulate the proliferation of immature retinal cells. [2] Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23-82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC0-8h), and maximum observed plasma concentration (Cmax) increased on days 1 and 15 with increasing pexidartinib doses, and time at Cmax (Tmax) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).[3] Background and objectives: Excessive adipose tissue macrophage accumulation in obesity has been implicated in mediating inflammatory responses that impair glucose homeostasis and promote insulin resistance. Colony-stimulating factor 1 (CSF1) controls macrophage differentiation, and here we sought to determine the effect of a CSF1 receptor inhibitor, Pexidartinib/PLX3397, on adipose tissue macrophage levels and understand the impact on glucose homeostasis in mice. Methods: A Ten-week-old mice were fed a chow or high-fat diet for 10 weeks and then treated with PLX3397 via oral gavage (50 mg/kg) every second day for 3 weeks, with subsequent monitoring of glucose tolerance, insulin sensitivity and assessment of adipose tissue immune cells. Results: PLX3397 treatment substantially reduced macrophage numbers in adipose tissue of both chow and high-fat diet fed mice without affecting total myeloid cell levels. Despite this, PLX3397 did not greatly alter glucose homeostasis, did not affect high-fat diet-induced increases in visceral fat cytokine expression (Il-6 and Tnfa) and had limited effect on the phosphorylation of the stress kinases JNK and ERK and macrophage polarization. Conclusions: Our results indicate that macrophage infiltration of adipose tissue induced by a high-fat diet may not be the trigger for impairments in whole body glucose homeostasis, and that anti-CSF1 therapies are not likely to be useful as treatments for insulin resistance. [4] Purpose: Peripheral T-cell lymphomas are clinically aggressive and usually fatal, as few complete or durable remissions are achieved with currently available therapies. Recent evidence supports a critical role for lymphoma-associated macrophages during T-cell lymphoma progression, but the specific signals involved in the cross-talk between malignant T-cells and their microenvironment are poorly understood. Colony-stimulator factor 1 receptor (CSF1R, CD115) is required for the homeostatic survival of tissue-resident macrophages. Interestingly, it’s aberrant expression has been reported in a subset of tumors. In this manuscript we evaluated its expression and oncogenic role in T-cell lymphomas. Experimental Design: Loss-of-function studies, including pharmacologic inhibition with a clinically available tyrosine-kinase inhibitor, Pexidartinib, were performed in multiple in vitro and in vivo models. In addition, proteomic and genomic screenings were performed to discover signaling pathways that are activated downstream of CSF1R signaling. Results: We observed that CSF1R is aberrantly expressed in many T-cell lymphomas, including a significant number of peripheral and cutaneous T-cell lymphomas. Colony-stimulating factor 1 (CSF1), in an autocrine or paracrine-dependent manner, leads to CSF1R autophosphorylation and activation in malignant T-cells. Furthermore, CSF1R signaling was associated with significant changes in gene expression and in the phosphoproteome, implicating PI3K/AKT/mTOR in CSF1R-mediated T-cell lymphoma growth. We also demonstrated that inhibition of CSF1R in-vivo and in-vitro models is associated with decreased T-cell lymphoma growth. Conclusions: Collectively, these findings implicate CSF1R in T-cell lymphomagenesis and have significant therapeutic implications. [5] |
Molecular Formula |
C20H15CLF3N5
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Molecular Weight |
417.81
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Exact Mass |
417.096
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Elemental Analysis |
C, 57.49; H, 3.62; Cl, 8.49; F, 13.64; N, 16.76
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CAS # |
1029044-16-3
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Related CAS # |
Pexidartinib hydrochloride;2040295-03-0
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PubChem CID |
25151352
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Appearance |
Yellow solid powder
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Density |
1.5±0.1 g/cm3
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Boiling Point |
580.0±50.0 °C at 760 mmHg
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Flash Point |
304.6±30.1 °C
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Vapour Pressure |
0.0±1.6 mmHg at 25°C
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Index of Refraction |
1.662
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LogP |
4.77
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Hydrogen Bond Donor Count |
2
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Hydrogen Bond Acceptor Count |
7
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Rotatable Bond Count |
5
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Heavy Atom Count |
29
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Complexity |
537
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Defined Atom Stereocenter Count |
0
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SMILES |
ClC1C([H])=NC2=C(C=1[H])C(=C([H])N2[H])C([H])([H])C1=C([H])N=C(C([H])=C1[H])N([H])C([H])([H])C1=C([H])N=C(C(F)(F)F)C([H])=C1[H]
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InChi Key |
JGWRKYUXBBNENE-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C20H15ClF3N5/c21-15-6-16-14(10-28-19(16)29-11-15)5-12-2-4-18(26-7-12)27-9-13-1-3-17(25-8-13)20(22,23)24/h1-4,6-8,10-11H,5,9H2,(H,26,27)(H,28,29)
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Chemical Name |
5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine
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Synonyms |
Pexidartinib; CML-261; FP-113; PLX3397; PLX 3397; CML 261; CML261; PLX-3397;FP 113; FP113; Pexidartinib (PLX3397); CML-261; Pexidartinib [INN]; trade name: Turalio
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Solubility (In Vivo) |
Solubility in Formulation 1: 5 mg/mL (11.97 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.98 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.98 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (4.98 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly. Solubility in Formulation 5: 10% DMSO+40% PEG 300+ddH2O: 15 mg/mL |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.3934 mL | 11.9672 mL | 23.9343 mL | |
5 mM | 0.4787 mL | 2.3934 mL | 4.7869 mL | |
10 mM | 0.2393 mL | 1.1967 mL | 2.3934 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT02975700 | Active Recruiting |
Drug: PLX3397 | Melanoma | Daiichi Sankyo Co., Ltd. | January 2017 | Not Applicable |
NCT04488822 | Active Recruiting |
Drug: Pexidartinib | Tenosynovial Giant Cell Tumor | Daiichi Sankyo Co., Ltd. | September 25, 2020 | Phase 3 |
NCT04703322 | Recruiting | Drug: Pexidartinib | Tenosynovial Giant Cell Tumor | Daiichi Sankyo Co., Ltd. | March 15, 2021 | Phase 2 |
NCT04635111 | Recruiting | Drug: TURALIO™ | Hepatotoxicity Tenosynovial Giant Cell Tumor |
Daiichi Sankyo, Inc. | January 7, 2021 | |
NCT02390752 | Recruiting | Drug: Turalio | Sarcoma Neurofibroma, Plexiform |
National Cancer Institute (NCI) |
April 29, 2015 | Phase 1 |
Combined PLX3397 and PTX treatment inhibits metastasis in a CD8-dependent manner. Cancer Discov. 2011 Jun 1; 1: 54–67. td> |
PTX in combination with PLX3397 induces antitumor T-cell response. Cancer Discov. 2011 Jun 1; 1: 54–67. td> |
CD68/CD4/CD8 immune signature is an independent prognostic indicator of breast cancer survival. Cancer Discov. 2011 Jun;1(1):54-67. td> |