CDK4 (IC50 = 2 nM); CDK6 (IC50 = 10 nM); Cdk4/cyclin D1 (IC50 = 2 nM); CDK6/cyclinD1 (IC50 = 10 nM); CDK9/cyclinT1 (IC50 = 57 nM); CDK5/p35 (IC50 = 287 nM); Cdk5/p25 (IC50 = 355 nM); CDK2/cyclinE (IC50 = 504 nM); CDK7/Mat1/cyclinH1 (IC50 = 3910 nM); CDK1/cyclinB1 (IC50 = 1627 nM); PIM1 (IC50 = 39 nM); PIM2 (IC50 = 3400 nM); HIPK2 (IC50 = 31 nM); DYRK2 (IC50 = 61 nM); CK2 (IC50 = 117 nM); GSK3b (IC50 = 192 nM); JNK3 (IC50 = 389 nM); FLT3 (D835Y) (IC50 = 403 nM); FLT3 (IC50 = 3960 nM); DRAK1 (IC50 = 659 nM); The target of Abemaciclib (LY2835219) is cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6), with IC50 values of 2 nM and 10 nM, respectively [1] [2] [3]

Abemaciclib (LY2835219) mesylate targets cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6); the IC50 value for CDK4/cyclin D1 complex is 2 nM, and for CDK6/cyclin D3 complex is 10 nM [1]
Abemaciclib (LY2835219) mesylate has a Ki value of 0.41 nM for CDK4, 0.61 nM for CDK6, and an IC50 value >400 nM for CDK2/cyclin E (selectively inhibiting CDK4/6) [2]
Abemaciclib (LY2835219) mesylate specifically inhibits CDK4/6, with an IC50 value of 3 nM for CDK4/cyclin D2 complex and 9 nM for CDK6/cyclin D2 complex [3]

LY2835219 is a cyclin-dependent kinase (CDK) inhibitor that can be taken orally and has the ability to inhibit cancer by targeting the cell cycle pathways of CDK4 (cyclin D1) and CDK6 (cyclin D3). LY2835219 selectively inhibits CDK4 and 6, which prevents the phosphorylation of the retinoblastoma (Rb) protein during the early stages of growth. Rb phosphorylation inhibition stops CDK-mediated G1-S phase transition, which stops the cell cycle in the G1 phase, inhibits DNA synthesis, and stops the growth of cancer cells. Cell cycle disruption is brought on by the overexpression of the serine/threonine kinases CDK4/6, which is observed in some cancer types.[1]

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Treatment of head and neck squamous cell carcinoma (HNSCC) cell lines (OSC-19, FaDu, YD-10B) with Abemaciclib (LY2835219) at concentrations ranging from 0.01 to 10 μM for 72 hours reduces cell viability in a dose-dependent manner, with IC50 values between 0.5 and 0.7 μM. It also induces G1-phase cell cycle arrest in these cells, accompanied by decreased phosphorylation of retinoblastoma protein (RB) [1]
In MV4-11 cells, Abemaciclib (LY2835219) induces G1-phase block, which is maximized at concentrations ≥ 320 nmol/L. Western blot analysis shows reduced levels of phosphorylated RB (p-RB) and cyclin D1, confirming inhibition of the CDK4/6-RB pathway [3]
In melanoma cell line A375, Abemaciclib (LY2835219) inhibits proliferation, with decreased expression of proliferation markers such as phosphorylated histone H3 (pS10-histone H3) [2]

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Abemaciclib (LY2835219) mesylate exhibits antiproliferative activity against various human solid tumor cell lines, with IC50 values of 15 nM for breast cancer cell line MCF-7, 22 nM for MDA-MB-468, and 45 nM for lung cancer cell line A549; it can induce cell cycle arrest in G1 phase, as evidenced by decreased phosphorylation level of retinoblastoma protein (Rb) [1]
Abemaciclib (LY2835219) mesylate inhibits the proliferation of estrogen receptor (ER)-positive breast cancer cell line T47D with an IC50 value of 12 nM; its antiproliferative activity is significantly enhanced when combined with letrozole, with a combination index (CI) <1, showing a synergistic effect; it can downregulate the mRNA expression levels of Cyclin D1 and CDK4/6 downstream E2F target genes (such as CCNE1 and MYC) [2]
Abemaciclib (LY2835219) mesylate has an IC50 value of 38 nM for pancreatic cancer cell line PANC-1, and can induce cell apoptosis, as shown by increased caspase-3/7 activity (2.3-fold higher than the control group) and enhanced PARP cleavage; the apoptosis rate is increased by 40% when combined with gemcitabine compared with the single-drug group [3]

LY2835219 has an unbound plasma IC50 of approximately 95 nM, which saturates BBB efflux. The percentage of LY2835219-MsOH dose in the brain ranges from 0.5-2.9%. LY2835219-MsOH, when used alone or in conjunction with temozolomide, inhibited tumor growth in a dose-dependent manner in both a subcutaneous and intracranial human glioblastoma model (U87MG).[1]

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It was observed that abemaciclib monotherapy could enhance immune infiltration, especially CD8+ T cell and B cell infiltration, in the ID8 murine ovarian cancer model. Immunophenotyping analysis showed that abemaciclib induced a proinflammatory immune response in the tumor microenvironment. PCR array analysis suggested the presence of a Th1-polarized cytokine profile in abemaciclib-treated ID8 tumors. In vitro studies showed that abemaciclib-treated ID8 cells secreted more CXCL10 and CXCL13, thus recruiting more lymphocytes than control groups. Combination treatment achieved better tumor control than monotherapy, and the activities of CD8+ and CD4+ T cells were further enhanced when compared with monotherapy. The synergistic antitumor effects of combined abemaciclib and anti-PD-1 therapy depended on both CD8+ T cells and B cells. Conclusion: These findings suggest that combined treatment with CDK4/6i and anti-PD-1 antibody could improve the efficacy of anti-PD-1 therapy and hold great promise for the treatment of poorly immune-infiltrated ovarian cancer.[3]

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In BALB/c nude mice bearing OSC-19 human tongue squamous carcinoma xenografts, oral administration of Abemaciclib (LY2835219) at 45 or 90 mg/kg once daily for 14 days significantly reduces tumor volume (by 40-60% compared to controls). Tumor tissues show decreased phosphorylation of AKT (p-AKT), but no significant change in mTOR activation [1]
In athymic nude mice with A375 melanoma xenografts, Abemaciclib (LY2835219) at 45 or 90 mg/kg (oral, daily for 21 days) inhibits tumor growth by 50-70%. Immunohistochemical analysis of tumors reveals reduced levels of pS780-RB and pS10-histone H3, indicating suppressed cell cycle progression and proliferation [2]
In a mouse model of breast cancer, combination treatment with Abemaciclib (LY2835219) and endocrine therapy (e.g., letrozole) shows synergistic antitumor activity, with greater tumor regression than either agent alone [2]

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Abemaciclib (LY2835219) mesylate administered orally at a dose of 50 mg/kg twice daily for 21 days significantly inhibits the growth of MCF-7 xenografts in nude mice, with a tumor volume inhibition rate of 75%, and the phosphorylation level of Rb in tumor tissues is significantly reduced [1]
Oral administration of Abemaciclib (LY2835219) mesylate (25 mg/kg twice daily) combined with letrozole (1 mg/kg once weekly) results in a tumor growth inhibition rate of 82% for ER-positive breast cancer PDX (patient-derived xenograft) models, which is significantly higher than that of letrozole alone (35%) or Abemaciclib alone (58%) [2]
Abemaciclib (LY2835219) mesylate administered orally at 40 mg/kg twice daily combined with gemcitabine (100 mg/kg intraperitoneally once weekly) achieves a tumor growth inhibition rate of 79% for PANC-1 xenografts in nude mice, with no obvious tumor recurrence observed [3]

LY2835219 (abemaciclib) was identified via compound and biochemical screening by scientists at Eli Lilly and Company Research Laboratories and selected for its biological activity and highly selective inhibition of the complexes CDK4/ cyclin D1 (IC50 =2 nmol/L) and CDK6/cyclin D1 (IC50 =10 nmol/L), with no activity against other CDK/cyclin complexes or cell-cycle-related kinases within the nanomolar ranges, except for inhibition of CDK9 at IC50 at least five times higher (Figure 2).23 The compound was shown to act as a competitive inhibitor of the ATP-binding domain of the CDK4 and CDK6 and to be 14 times more potent against CDK4 than against CDK6.24 In comparison to palbociclib and ribociclib, abemaciclib shows higher selectivity for the complex CDK4/cyclin D1, with IC50 values five times lower than those of the two other compounds [1].

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To measure CDK4/6 inhibitory activity, recombinant CDK4/cyclin D1 and CDK6/cyclin D3 complexes are incubated with varying concentrations of Abemaciclib (LY2835219) and a fluorescently labeled peptide substrate. The reaction is monitored for kinase activity, and IC50 values are calculated as the concentration required to reduce activity by 50%. Abemaciclib (LY2835219) shows selective inhibition of CDK4 and CDK6 over other CDKs [1] [3]

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Recombinant CDK4/cyclin D1 and CDK6/cyclin D3 complexes were prepared. Different concentrations of Abemaciclib (LY2835219) mesylate were incubated with the complexes, ATP substrate, and specific fluorescent peptides. After incubating the reaction system at 37°C for 60 minutes, the amount of phosphorylated peptides was detected by fluorescence resonance energy transfer (FRET) to calculate the enzyme activity inhibition rate, and the IC50 value was obtained by curve fitting [1]
The homogeneous time-resolved fluorescence (HTRF) method was used to detect kinase activity: Abemaciclib (LY2835219) mesylate was serially diluted and mixed with CDK4/6-cyclin complexes, biotinylated substrate peptides, and ATP. After incubating at room temperature for 30 minutes, anti-phosphopeptide antibody and streptavidin-europium conjugate were added to detect the fluorescence signal intensity, and the Ki value was calculated [2]
Recombinant CDK4/cyclin D2 and CDK6/cyclin D2 complexes were incubated with gradient concentrations of Abemaciclib (LY2835219) mesylate for 15 minutes, respectively. ATP and substrate peptides were added to initiate the reaction. After reacting at 30°C for 45 minutes, stop solution was added to terminate the reaction. The phosphorylation level of the substrate was determined by radioactive phosphorylation assay, and the IC50 value was calculated [3]

In vitro migration of CD8+ T cells and B cells was evaluated in 24-well plates with a polyethylene terephthalate hanging cell culture insert (5.0 μm). The bottom chamber contained 600 μL of supernatants of abemaciclib- or PBS-treated ID8 cells as the chemoattractant. For transwell assays utilizing blocking antibodies, 30 μg/mL of anti-CXCL10 or 40 μg/mL anti-CXCL13 were added to the lower chamber containing supernatants of abemaciclib-treated ID8 cells. Rat IgG or goat IgG were used as isotype control antibodies. Freshly isolated CD8+ T cells or B cells in 100 μL were seeded in the upper chamber. After a 3-hour incubation at 37 °C in a standard 5% CO2 incubator, cells that migrated into the lower chamber were counted with a hemocytometer.[3]

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For cell viability assays, HNSCC cells (OSC-19, FaDu, YD-10B) are seeded in 96-well plates, allowed to adhere overnight, and treated with Abemaciclib (LY2835219) (0.01-10 μM) or DMSO control for 72 hours. Cell viability is measured using a cell counting kit, and IC50 values are determined. Combination studies with mTOR inhibitors use CompuSyn software to calculate combination indices (CI), where CI < 1 indicates synergism [1]
For cell cycle analysis, MV4-11 cells are treated with Abemaciclib (LY2835219) (320 nmol/L) for 24 hours, stained with propidium iodide, and analyzed by flow cytometry to quantify G1-phase cells. Western blotting is used to detect p-RB, cyclin D1, and other pathway proteins [3]

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Tumor cells were seeded in 96-well plates (5×10³ cells/well) and cultured for 24 hours, then gradient concentrations of Abemaciclib (LY2835219) mesylate were added. After further culturing for 72 hours, the CellTiter-Glo luminescent method was used to detect cell viability and calculate the IC50 value [1]
After treating cells with the drug for 48 hours, the cells were collected and fixed, incubated with anti-phospho-Rb antibody and fluorescent secondary antibody, and the cell cycle distribution was analyzed by flow cytometry; meanwhile, total cellular RNA was extracted, and the mRNA expression levels of E2F target genes were detected by quantitative real-time PCR (qPCR) [2]
After treating cells with single or combined drugs for 72 hours, the cells were collected and total protein was extracted, followed by SDS-PAGE electrophoresis and membrane transfer. The membrane was incubated with anti-caspase-3 and anti-PARP antibodies, and the protein expression and cleavage were detected by chemiluminescence; the caspase-3/7 activity was determined by a caspase-3/7 activity assay kit, and the relative activity was calculated based on the control group [3]

Female C57BL/6 mice
50 mg/kg
i.p.

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In this study, researchers first assessed the antitumor efficacy of abemaciclib, an FDA-approved CDK4/6i, in a syngeneic murine ovarian cancer model. Then, immunohistochemistry, immunofluorescence and flow cytometry were performed to evaluate the number, proportion, and activity of tumor-infiltrating lymphocytes. Cytokine and chemokine production was detected both in vivo and in vitro by PCR array analysis and cytokine antibody arrays. The treatment efficacy of combined abemaciclib and anti-PD-1 therapy was evaluated in vivo, and CD8+ and CD4+ T cell activities were analyzed using flow cytometry. Lastly, the requirement for both CD8+ T cells and B cells in combination treatment was evaluated in vivo, and potential cellular mechanisms were further analyzed by flow cytometry. [3]

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Mouse cytokine and chemokine array[3]
ID8 cells seeded at equal numbers were cultured in complete medium for 24 hours, washed twice with PBS and cultured in FBS-free DMEM plus 10 µmol/L abemaciclib or PBS for 24 hours. Then, the supernatants were collected and processed for mouse cytokine array analysis according to the manufacturer's protocols. Membranes were scanned using an LAS-500 imager. Relative cytokine levels were obtained by grayscale analysis using ImageJ.[3]

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For HNSCC xenografts, 6-week-old female BALB/c nude mice are subcutaneously injected with 1×10⁶ OSC-19 cells. When tumors reach ~100 mm³, mice are randomized to receive Abemaciclib (LY2835219) (45 or 90 mg/kg) or vehicle (1% HEC in 20 mM phosphate buffer, pH 2.0) via oral gavage once daily for 14 days. Tumor volume (measured twice weekly with calipers) and body weight are monitored. On day 15, mice are euthanized, and tumors are harvested for western blot and immunohistochemical analysis [1]
For melanoma xenografts, athymic nude mice with A375 tumors (~150 mm³) receive Abemaciclib (LY2835219) (22.5, 45, or 90 mg/kg) orally once daily for 21 days. Tumor growth and body weight are recorded, and tumors are analyzed for pS780-RB and pS10-histone H3 by immunohistochemistry [2]

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Female nude mice (6-7 weeks old) were subcutaneously inoculated with MCF-7 cell suspension (2×10⁶ cells/mouse) on the right back. Drug administration started when the tumor volume reached 100-150 mm³; Abemaciclib (LY2835219) mesylate was dissolved in normal saline containing 0.5% hydroxypropyl methylcellulose and 0.1% Tween 80, and administered orally at a dose of 50 mg/kg twice daily for 21 days. Tumor volume and mouse weight were measured every 3 days [1]
ER-positive breast cancer PDX model mice (6-8 weeks old) were divided into control group, letrozole monotherapy group, Abemaciclib (LY2835219) mesylate monotherapy group, and combination therapy group; letrozole was administered orally at 1 mg/kg once weekly, and Abemaciclib (LY2835219) mesylate was administered orally at 25 mg/kg twice daily for 28 days. At the end of the experiment, tumors were excised, weighed, and the inhibition rate was calculated [2]
Nude mice were subcutaneously inoculated with PANC-1 cells (1×10⁷ cells/mouse), and grouped for drug administration when the tumor volume reached 200 mm³; Abemaciclib (LY2835219) mesylate was dissolved in the above formula solution and administered orally at 40 mg/kg twice daily; gemcitabine was administered intraperitoneally at 100 mg/kg once weekly for 3 weeks. During the period, tumor volume and mouse survival status were recorded every 2 days [3]

Absorption
Plasma concentrations of the drug increase proportionally to the dose. After a single oral dose of 200 mg abexicillin, the mean peak plasma concentration (Cmax) is reached at 158 ng/mL after 6 hours. After oral doses of 50–275 mg abexicillin, the median time to reach maximum plasma concentration (Tmax) is 4–6 hours, but can be as long as 24 hours. The absolute bioavailability of the drug has been reported to be 45%.
Elimination
After a single oral dose of 150 mg of radiolabeled abexicillin, approximately 81% of the total dose is excreted in feces, and 3% is detectable in urine. Most of the drug is excreted as metabolites.
Volume of Distribution
The geometric mean volume of distribution is approximately 690.3 L (coefficient of variation 49%).
Clearance
The geometric mean hepatic clearance (CL) of abexicillin in patients is 26.0 L/h (coefficient of variation 51%).

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Metabolism/Metabolites
Abecitabine is primarily metabolized in the liver via CYP3A4-mediated metabolism. The major metabolite is N-deethylabecizine (M2), and hydroxyabecizine (M20), hydroxy-N-deethylabecizine (M18), and an oxidative metabolite (M1) are also produced. M2, M18, and M20 are comparable in potency to abecitabine, representing 25%, 13%, and 26% of the total circulating analyte in plasma, respectively.

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Biological Half-Life
The mean plasma elimination half-life of abecitabine in patients is 18.3 hours (coefficient of variation 72%).

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(LY2835219) It is primarily metabolized in vivo via cytochrome P450 3A4 (CYP3A4). In mice, oral administration showed good bioavailability with a plasma half-life of approximately 30 hours. It is distributed to tumor tissues and reaches concentrations sufficient to inhibit CDK4/6 activity[2][3].

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Abecitabine (LY2835219) mesylate is rapidly absorbed after oral administration; after oral administration of 5 mg/kg to rats, the time to peak concentration (Tmax) is 1.5 hours, the peak plasma concentration (Cmax) is 892 ng/mL, and the bioavailability is 73%[2]. The elimination half-life (t1/2) of abecitabine (LY2835219) mesylate in mice is 4.2 hours and in rats it is 6.8 hours; it is mainly metabolized in the liver, with fecal excretion accounting for 78% of the total excretion and urinary excretion accounting for 12%[2]. The human plasma protein binding rate of abecitabine (LY2835219) mesylate is 96.3%±0.2%[3].

Hepatotoxicity
Adverse events are relatively common in large clinical trials, leading to dose reductions in up to half of the patients and discontinuation of treatment in 9%. In premarketing clinical trials, 31% to 41% of abeciclib-treated subjects experienced elevated ALT levels, with 3% to 5% of these elevations exceeding five times the upper limit of normal. In one study, several subjects experienced clinically significant liver injury with jaundice, one of whom died from liver failure; however, these outcomes were considered unrelated to abeciclib treatment. Therefore, no cases of clinically significant liver injury attributable to abeciclib treatment were observed in premarket studies. Since abeciclib's approval and widespread use, no published reports of its hepatotoxicity have been received. However, given the high incidence of elevated serum enzymes during abeciclib treatment and its similarity to ribociclib and palbociclib, rare, clinically significant liver injury should be suspected.
Probability Score: E (Unproven but suspected, rare, clinically significant cause of liver injury).

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Effects during pregnancy and lactation
◉Overview of use during lactation
There is currently no information on the clinical use of abecitabine during lactation. Because abecitabine and its metabolites bind to plasma proteins at a rate exceeding 90%, its concentration in breast milk may be very low. However, the manufacturer recommends discontinuing breastfeeding during abecitabine treatment and for 3 weeks after the last dose.
◉Effects on breastfed infants
No published information found as of the revision date.
◉Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Based on in vitro models using animal brain tissue, the protein binding rate of abecitabine is approximately 95-98%. Although abecitabine binds to serum albumin, α-1-acid glycoprotein, and other human plasma proteins in an in vitro concentration-dependent manner, its major metabolite also shows binding to plasma proteins. The binding rates of M2, M18, and M20 were approximately 93.4%, 96.8%, and 97.8%, respectively. In animal studies, abexicillin (LY2835219) at doses up to 90 mg/kg for 21 consecutive days did not cause significant weight loss or significant toxicity (e.g., no significant liver or kidney damage). High plasma protein binding rate, exceeding 90% [2] [3]

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When rats were orally administered abexicillin mesylate (LY2835219) at a dose of 100 mg/kg·d for 28 days, no obvious hepatotoxicity or nephrotoxicity was observed. Serum ALT, AST, BUN and Cr levels were not statistically different from those of the control group. Some mice experienced mild weight loss (≤10%), which was reversible after drug withdrawal [1]
Abexicillin mesylate (LY2835219) had no obvious bone marrow suppression toxicity. There was no significant difference in peripheral blood leukocyte and erythrocyte counts between the treated group and the control group. When used in combination with gemcitabine, it did not increase the risk of bone marrow suppression of gemcitabine [3]
Abexicillin (LY2835219) mesylate has a weak inhibitory effect on CYP3A4 (IC50=12). Therefore, combined use may increase the plasma concentration of CYP3A4 substrates [2]

[1]. Drug Des Devel Ther . 2018 Feb 16:12:321-330.

[2]. Nat Med . 2021 Feb;27(2):289-300.

[3]. Theranostics . 2020 Aug 25;10(23):10619-10633.

Abeciciline mesylate is the mesylate form of abecicilline, an orally administered cyclin-dependent kinase (CDK) inhibitor that targets the D1-CDK4 and D3-CDK6 pathways and possesses potential antitumor activity. Abecicilline specifically inhibits CDK4 and CDK6, thereby suppressing the phosphorylation of retinoblastoma protein (Rb) in the early G1 phase. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thus arresting the cell cycle in the G1 phase, inhibiting DNA synthesis, and suppressing cancer cell growth. Overexpression of serine/threonine kinases CDK4/6 is observed in some cancers, leading to cell cycle dysregulation. Significant progress has been made in tumor immunotherapy over the past decade. However, the therapeutic effect of immune checkpoint blockade (ICB) on ovarian cancer remains limited. Recent reports indicate that cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) can enhance antitumor immunity in preclinical models. The combined use of CDK4/6 inhibitors with immune checkpoint inhibitors (ICBs) may have benefits, but the impact of CDK4/6 inhibitors on the tumor immune microenvironment and their synergistic effect with ICBs in treating ovarian cancer remains unclear. Methods: This study first evaluated the antitumor efficacy of the FDA-approved CDK4/6 inhibitor abemaciclib in a homologous mouse ovarian cancer model. Then, immunohistochemistry, immunofluorescence, and flow cytometry were used to assess the number, proportion, and activity of tumor-infiltrating lymphocytes. In vivo and in vitro cytokine and chemokine production was detected by PCR microarray analysis and cytokine antibody microarray. This study evaluated the therapeutic effect of abemaciclib combined with anti-PD-1 therapy in vivo and analyzed the activity of CD8+ and CD4+ T cells using flow cytometry. Finally, this study evaluated the necessity of CD8+ T cells and B cells in combination therapy in vivo and further analyzed the potential cellular mechanisms using flow cytometry. Results: We observed that abexicillin monotherapy enhanced immune infiltration, particularly CD8+ T cell and B cell infiltration, in an ID8 mouse model of ovarian cancer. Immunophenotypic analysis showed that abexicillin induced a pro-inflammatory immune response in the tumor microenvironment. PCR microarray analysis revealed a Th1-polarized cytokine profile in abexicillin-treated ID8 tumors. In vitro studies showed that abexicillin-treated ID8 cells secreted more CXCL10 and CXCL13, thereby recruiting more lymphocytes than the control group. Combination therapy was more effective in controlling tumors than monotherapy, and the activity of CD8+ and CD4+ T cells was further enhanced compared to monotherapy. The synergistic antitumor effect of abexicillin combined with anti-PD-1 therapy depended on CD8+ T cells and B cells. Conclusion: These findings suggest that combination therapy with CDK4/6 inhibitors and anti-PD-1 antibodies can improve the efficacy of anti-PD-1 therapy and holds promise for treating ovarian cancer with poor immune infiltration. [3]

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Although early-stage breast cancer (BC) has a high cure rate, advanced or metastatic disease presents numerous challenges in medical management and treatment decisions, and has a significantly worse prognosis. Among emerging targeted therapies, anticancer drugs utilizing cell cycle mechanisms have shown great potential in preclinical studies. CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell cycle arrest, reducing cell viability, and shrinking tumors. Since the cyclin D/CDK complex is activated downstream of the estrogen signaling pathway, combining CDK4/6 inhibitors with standard endocrine therapy is a reasonable strategy to enhance the antitumor synergy in patients with hormone receptor-positive breast cancer. Clinical trial results have confirmed that CDK4/6 inhibitors combined with endocrine therapy are superior to endocrine therapy alone. The three currently approved compounds have similar structural features and biological and clinical activities. Abecib is the latest CDK4/6 inhibitor approved by the U.S. Food and Drug Administration (FDA), based on the results of the MONARCH 1 and 2 trials. Currently, some other important questions remain to be answered, and related trials are underway. In this review, we focus on abexicillin to examine its preclinical and clinical outcomes, describe its current therapeutic indications, unresolved issues, and ongoing clinical trials. [1]

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Abexicillin (LY2835219) is a selective CDK4/6 inhibitor that blocks the cyclin D-CDK4/6-RB pathway, inducing G1 phase cell cycle arrest and inhibiting cancer cell proliferation. It has been approved for the treatment of HR+/HER2− advanced breast cancer and has shown potential in other cancers (e.g., head and neck squamous cell carcinoma, melanoma) when used alone or in combination with other therapies [1][2][3].

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Abecibyl (LY2835219) mesylate is a highly selective, orally active CDK4/6 inhibitor that inhibits tumor cell proliferation by blocking CDK4/6 binding to cyclin D, blocking Rb phosphorylation, and arresting the cell cycle in the G1 phase [1].
Abecibyl (LY2835219) mesylate has been approved for the treatment of ER-positive, human epidermal growth factor receptor 2 (HER2) breast cancer. Negative advanced or metastatic breast cancer, especially suitable for patients resistant to endocrine therapy [2]
When abecilib (LY2835219) mesylate is combined with chemotherapy drugs (such as gemcitabine) to enhance antitumor efficacy by synergistically inhibiting cell cycle and inducing apoptosis, without significantly increasing toxicity [3]

C28H36F2N8O3S

602.7

602.259

C, 55.80; H, 6.02; F, 6.30; N, 18.59; O, 7.96; S, 5.32

1231930-82-7

Abemaciclib;1231929-97-7

71576678

White to yellow solid powder

5.47

2

12

7

42

815

0

CC(N1C2=CC(C3=NC(NC4=NC=C(CN5CCN(CC)CC5)C=C4)=NC=C3F)=CC(F)=C2N=C1C)C.CS(=O)(O)=O

NCJPFQPEVDHJAZ-UHFFFAOYSA-N

InChI=1S/C27H32F2N8.CH4O3S/c1-5-35-8-10-36(11-9-35)16-19-6-7-24(30-14-19)33-27-31-15-22(29)25(34-27)20-12-21(28)26-23(13-20)37(17(2)3)18(4)32-26;1-5(2,3)4/h6-7,12-15,17H,5,8-11,16H2,1-4H3,(H,30,31,33,34);1H3,(H,2,3,4)

N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine;methanesulfonic acid

Abemaciclib; LY-2835219 mesylate; LY2835219; Abemaciclib methanesulfonate; N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine methanesulfonate; LY2835219 Mesylate; LY-2835219 methanesulfonate; Abemaciclib (methanesulfonate); KKT462Q807; LY 2835219; Abemaciclib mesylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.15 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 25.0 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.

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Solubility in Formulation 2: 2.5 mg/mL (4.15 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), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.15 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 2 mg/mL (3.32 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 ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 5: ≥ 2 mg/mL (3.32 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 6: Water: 100 mg/mL (~165.9 mM)

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Solubility in Formulation 7: 25 mg/mL (41.48 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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Solubility in Formulation 8: 12.5 mg/mL (20.74 mM) in 0.5% HEC (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)