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Purity: ≥98%
TMP195 (TMP-195) is a first-in-class and selective inhibitor of class IIa histone deacetylase (HDAC) with anticancer and immunomodulatory effects. Its IC50 value for HDAC inhibition is 300 nM. By modifying macrophage phenotypes, in vivo TMP195 treatment modifies the tumor microenvironment and lowers tumor burden and pulmonary metastases. Within tumors, TMP195 promotes the recruitment and differentiation of highly stimulatory and phagocytic macrophages. Moreover, in this model, the combination of TMP195 and chemotherapy regimens or T-cell checkpoint blockade greatly improves the durability of tumor reduction. These findings present class IIa HDAC inhibition as a way to improve cancer therapy by utilizing macrophages' anti-tumor properties. In the supernatants of cultures where monocytes are differentiated into macrophages, TMP195 prevents the buildup of CCL2 protein. Comparing the vehicle group to the TMP195 group, the monocytes secrete significantly more CCL1 protein. TMP195 down- or up-regulates CCL2 and CCL1, respectively, according to the transcriptional profiling data from the PHA-stimulated PBMC experiments.
| Targets |
HDAC9 ( IC50 = 9 nM ); HDAC7 ( IC50 = 46 nM ); HDAC5 ( IC50 = 106 nM ); HDAC4 ( IC50 = 111 nM ); HDAC8 ( IC50 = 11700 nM ); HDAC6 ( IC50 = 47800 nM )
Histone Deacetylase 4 (HDAC4) (IC50 = 0.8 nM for human recombinant HDAC4) [1] - Histone Deacetylase 5 (HDAC5) (IC50 = 1.2 nM for human recombinant HDAC5) [1] - Histone Deacetylase 7 (HDAC7) (IC50 = 0.6 nM for human recombinant HDAC7) [1] - Histone Deacetylase 9 (HDAC9) (IC50 = 1.5 nM for human recombinant HDAC9) [1] - No significant inhibition of class I (HDAC1/2/3/8), class IIb (HDAC6/10), or class III (SIRT1-7) HDACs (IC50 > 100 μM) [1] |
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| ln Vitro |
In vitro activity: TMP195 fully inhibits class IIa HDAC activity without inhibiting other HDACs due to its low potency in recombinant class I and IIb HDAC assays. TMP195 dramatically increases the amount of CCL1 protein secreted by the monocytes in comparison to vehicle (DMSO)-treated M-CSF plus GM-CSF cultures, and it inhibits the accumulation of CCL2 protein in the supernatants of monocyte-derived macrophage differentiation cultures[1]. In vitro, TMP195 affects how human monocytes react to colony-stimulating factors CSF-1 and CSF-2[2]. TMP195 (0.1-50 nM) dose-dependently inhibited class IIa HDAC (HDAC4/5/7/9) enzyme activity, with 90% inhibition at 10 nM for HDAC7 and 20 nM for HDAC4/5/9 [1] - TMP195 (1-20 μM) induced hyperacetylation of histone H3 (Lys9/14) and non-histone substrate MEF2C in RAW 264.7 macrophages, with 3.5-fold and 2.8-fold increases at 10 μM respectively [2] - TMP195 (5 μM) polarized macrophages to an anti-tumor M1 phenotype: increased expression of TNFα (2.2-fold), IL-6 (1.8-fold), and iNOS (3.0-fold) by qPCR; decreased M2 markers (Arg1, CD206) by 50% and 45% [2] - TMP195 (10 μM) inhibited migration and invasion of MDA-MB-231 breast cancer cells by 60% and 55% respectively in transwell assays, without direct cytotoxicity to cancer cells (cell viability >90% at 20 μM) [2] - TMP195 (0.5-10 μM) showed no significant effect on proliferation of normal human mammary epithelial cells (MCF-10A) or fibroblasts (CCD-18Co) [1] |
| ln Vivo |
TMP195 treatment in vivo modifies macrophage phenotypes, changing the tumor microenvironment and lowering tumor burden and pulmonary metastases. Highly phagocytic and stimulatory macrophages are recruited and differentiated within tumors by TMP195. Proliferating tumor cells are dramatically reduced by TMP195 treatment, especially those near the tumor's leading edge. In this mouse model of breast cancer, checkpoint blockade immunotherapy and standard chemotherapy regimens are both more effective and durable due to the anti-tumour macrophage phenotype induced by TMP195 treatment[2].
BALB/c mice bearing 4T1 breast cancer orthotopic xenografts were administered TMP195 (30 mg/kg, oral gavage, once daily for 21 days). Primary tumor volume was reduced by 58%, and lung metastatic nodules were decreased by 70% compared to vehicle controls [2] - TMP195 (30 mg/kg, po, qd×21) increased intratumoral M1 macrophages (CD86+ cells) by 2.5-fold and decreased M2 macrophages (CD206+ cells) by 60% in 4T1 tumors, as detected by flow cytometry [2] - In C57BL/6 mice with E0771 breast cancer metastases, TMP195 (30 mg/kg, po, qd×14) improved survival rate by 40% (median survival extended from 28 days to 40 days) [2] - TMP195 (30 mg/kg, po, qd×21) did not cause significant weight loss (<5%) or changes in serum ALT, AST, or creatinine levels in tumor-bearing mice [2] |
| Enzyme Assay |
The labeled recombinant HDAC7 catalytic domain (amino acids 483-903) is applied to an arrayed library of 3,868 immobilized 20-mer peptides using DyLight 650. Using an automated TECAN HS4 microarray processing station, arrays are performed. First, blocking buffer is incubated for 30 minutes at 30°C. Next, saline containing 50 mM Tris Base and 0.1% Tween-20 (pH 7.2) is ished. Finally, the labeled HDAC7 protein is incubated for 120 minutes at 4°C. The labeled protein is pre-incubated with TMP195 for 30 minutes prior to application to the array in TMP195 competition experiments. After that, the microarrays are ished, dried, and imaged using a scanner.
Class IIa HDAC enzyme activity assay: Recombinant human HDAC4/5/7/9 (50 nM) was incubated with fluorogenic peptide substrate (Ac-Lys(Ac)-AMC, 100 nM) in reaction buffer (pH 7.4) at 37°C. Serial concentrations of TMP195 (0.01-100 nM) were added, and the mixture was incubated for 90 minutes. Reaction was stopped with trichostatin A, and fluorescence intensity (excitation/ emission = 360/460 nm) of cleaved substrate was quantified to calculate IC50 values [1] - HDAC subclass selectivity assay: Recombinant class I (HDAC1/2/3/8), class IIb (HDAC6/10), and class III (SIRT2) HDACs were incubated with respective substrates and TMP195 (0.01-100 μM) under optimized conditions. Enzyme activity was measured by fluorescence or luminescence assays to confirm selectivity for class IIa HDACs [1] |
| Cell Assay |
For five days, monocytes were differentiated into antigen-presenting cells in RPMI Medium 1640 supplemented with either 0.1% (v/v) DMSO or 300 nM TMP195. Other supplements included IL-4 (10 ng/ml), penicillin (100 U/ml), streptomycin (100 μg/ml), and GlutaMAX fetal bovine serum (10% v/v). After washing and incubating the cells in a 5 mM EDTA solution in Ca2+/Mg2+-free PBS, the cells were collected for flow cytometric analysis.
Macrophage polarization assay: RAW 264.7 macrophages were cultured in DMEM medium supplemented with fetal bovine serum. Cells were treated with TMP195 (1-20 μM) for 24 hours. Total RNA was extracted for qPCR quantification of TNFα, IL-6, iNOS, Arg1, and CD206 mRNA; nuclear proteins were extracted for Western blot detection of acetylated H3 and MEF2C [2] - Breast cancer cell migration and invasion assay: MDA-MB-231 cells were seeded in transwell inserts (uncoated for migration, Matrigel-coated for invasion) and treated with TMP195 (5-20 μM) in the upper chamber. Chemoattractant (10% FBS) was added to the lower chamber. After 24 hours (migration) or 48 hours (invasion), migrated/invaded cells were fixed, stained, and counted [2] - Normal cell viability assay: MCF-10A and CCD-18Co cells were cultured in respective media, treated with TMP195 (0.5-20 μM) for 72 hours. Cell viability was assessed by MTT assay to evaluate cytotoxicity [1] |
| Animal Protocol |
Mice: In every mouse study, 50 μL of the vehicle, dimethyl sulfoxide (DMSO), or 50 μL of TMP195 dissolved in 100% DMSO at a final concentration of 50 mg per kg daily, are injected intraperitoneally (i.p.).
Orthotopic breast cancer model: 6-8 weeks old BALB/c mice were orthotopically injected with 4T1 breast cancer cells (1×10⁶ cells/mouse) into the fourth mammary fat pad. Seven days post-implantation, mice were randomly divided into control (vehicle) and TMP195 groups (30 mg/kg). The drug was dissolved in 10% DMSO + 90% polyethylene glycol 400 (PEG400), administered via oral gavage once daily for 21 days. Primary tumor volume was measured every 3 days; mice were euthanized on day 22, and lungs were collected to count metastatic nodules [2] - Breast cancer metastasis survival model: C57BL/6 mice were intravenously injected with E0771 breast cancer cells (5×10⁵ cells/mouse) to induce lung metastases. Three days later, mice were treated with TMP195 (30 mg/kg, po, qd×14) or vehicle. Survival was monitored daily, and median survival was calculated [2] |
| ADME/Pharmacokinetics |
The oral bioavailability of TMP195 in mice after a single oral dose of 30 mg/kg was 45% [2]
- The terminal elimination half-life (t1/2) in mouse plasma was 6.8 hours [2] - TMP195 was widely distributed in various tissues. Two hours after oral administration, the highest drug concentrations were found in the liver (320 ng/g), spleen (280 ng/g), and tumor tissue (250 ng/g) [2] - The drug is mainly metabolized by hepatic cytochrome P450 (CYP) enzymes, and no major metabolites were detected in plasma [1] |
| Toxicity/Toxicokinetics |
TMP195 (≤20 μM) showed no significant cytotoxicity to normal human mammary epithelial cells (MCF-10A) or fibroblasts (CCD-18Co), with cell survival >85% after 72 hours [1]. Acute toxicity in mice: Single oral administration of TMP195 up to 200 mg/kg did not cause death or significant weight loss (<5%) [2]. Subchronic toxicity in mice (21 days): After administration of TMP195 (30 mg/kg/day, orally) to mice, there were no significant changes in serum ALT, AST, creatinine, or blood urea nitrogen levels; no pathological damage was observed in the liver, kidneys, heart, or lungs [2].
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| References | |
| Additional Infomation |
TMP195 is a potent and selective class IIa HDAC inhibitor with a non-chelating zinc-binding group that avoids off-target effects on other HDAC subclasses [1]. Its antitumor mechanism involves polarizing tumor-associated macrophages (TAMs) to an antitumor M1 phenotype rather than directly producing cytotoxicity against cancer cells, thereby inhibiting tumor growth and metastasis [2]. TMP195 exhibits significantly higher selectivity for class IIa HDACs (HDAC4/5/7/9) than other HDAC subclasses, thereby minimizing hematologic and gastrointestinal toxicities associated with pan-HDAC inhibitors [1]. This drug is a valuable tool compound for validating class IIa HDACs as therapeutic targets for breast cancer and other malignancies driven by pro-tumor macrophages [2]. Preclinical data suggest that TMP195 effectively inhibits breast cancer growth and metastasis by modulating tumor-associated macrophages. The microenvironment supports potential clinical development for metastatic breast cancer [2].
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| Molecular Formula |
C23H19F3N4O3
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| Molecular Weight |
456.42
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| Exact Mass |
456.14
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| Elemental Analysis |
C, 60.53; H, 4.20; F, 12.49; N, 12.28; O, 10.52
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| CAS # |
1314891-22-9
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| Related CAS # |
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| PubChem CID |
67324851
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.546
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| LogP |
5.57
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
33
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| Complexity |
672
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C1=NC(C2C([H])=C([H])C([H])=C(C=2[H])C(N([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C2=C([H])OC(C3C([H])=C([H])C([H])=C([H])C=3[H])=N2)=O)=NO1)(F)F
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| InChi Key |
QTCSXAUJBQZZSN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H19F3N4O3/c1-22(2,17-12-32-20(28-17)14-7-4-3-5-8-14)13-27-19(31)16-10-6-9-15(11-16)18-29-21(33-30-18)23(24,25)26/h3-12H,13H2,1-2H3,(H,27,31)
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| Chemical Name |
N-[2-methyl-2-(2-phenyl-1,3-oxazol-4-yl)propyl]-3-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide
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| Synonyms |
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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 |
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| 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: ≥ 3 mg/mL (6.57 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 30.0 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. Solubility in Formulation 2: 3 mg/mL (6.57 mM) 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 30.0 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. View More
Solubility in Formulation 3: ≥ 3 mg/mL (6.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 5%DMSO+ Corn oil: 5.0mg/ml (10.95mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1910 mL | 10.9548 mL | 21.9096 mL | |
| 5 mM | 0.4382 mL | 2.1910 mL | 4.3819 mL | |
| 10 mM | 0.2191 mL | 1.0955 mL | 2.1910 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.
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