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Purity: ≥98%
BMS-986158 (BMS986158; BMS 986158) is a novel, potent and selective BET (bromodomain and extra-terminal) protein inhibitor with potential antineoplastic activity. BET proteins (BRD2, BRD3, BRD4 and BRDT) are transcriptional regulators that bind to acetylated lysines on the tails of histones H3 and H4, and regulate chromatin structure and function; they play an important role in the modulation of gene expression during development and cellular growth. As a BET inhibitor, BMS-986158 acts by binding to the acetyl-lysine binding site in the BRD of BET proteins, thereby preventing the interaction between BET proteins and acetylated histones, which disrupts chromatin remodeling and prevents the expression of certain growth-promoting genes, resulting in an inhibition of tumor cell growth.
| Targets |
BMS-986158 targets bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family (BRD4 BD1: IC50 = 3.2 nM for bromodomain binding via AlphaScreen assay [1]
; BRD4 BD2: IC50 = 4.8 nM for bromodomain binding [1] ; >50-fold selectivity over BRD2 (IC50 = 180 nM) and BRD3 (IC50 = 210 nM) [1] ; no significant binding to non-BET bromodomains (e.g., BRD7, BRD9) with IC50 > 1000 nM [1] ) |
|---|---|
| ln Vitro |
BMS-986158 exhibits potential anti-tumor efficacy as an inhibitor of the ecto-terminal domain (BET) and bromodomain (BRD) protein families. Following injection, the BET inhibitor BMS-986158 binds to the BET protein BRD's acetyl lysine binding site, blocking the BET protein's ability to interact with acetylated histones. Tumor cell development is inhibited as a result of this disruption of chromatin remodeling and suppression of the expression of several growth-promoting genes [2].
1. BMS-986158 potently inhibited BRD4 bromodomain binding to acetylated histone H4 (H4K5ac/K8ac) peptide, with IC50 values of 3.2 nM (BD1) and 4.8 nM (BD2) in AlphaScreen assays; it exhibited >50-fold selectivity for BRD4 over other BET family members (BRD2, BRD3) and no off-target binding to non-BET bromodomains at concentrations up to 1 μM [1] 2. In human pancreatic cancer cell lines (PANC-1, MiaPaCa-2), BMS-986158 (10-1000 nM) dose-dependently suppressed cell proliferation with IC50 values of 65 nM (PANC-1) and 82 nM (MiaPaCa-2) after 72-hour treatment (CCK-8 assay) [1] 3. The compound (100 nM) downregulated the expression of pro-inflammatory cytokines/chemokines (CCL2, CSF1, IL-6) in PANC-1 cells by 60-75% at the mRNA level (qPCR) and 55-70% at the protein level (ELISA), key mediators of cancer cell-macrophage crosstalk [1] 4. Western blot analysis in PANC-1 cells showed that BMS-986158 (50 nM) inhibited BRD4-mediated transcriptional activation by reducing phosphorylation of RNA polymerase II (Ser2) by 65% and downregulating c-Myc (a BRD4 target gene) by 70% within 24 hours [1] 5. In cancer cell-macrophage co-culture models (PANC-1 + THP-1-derived macrophages), BMS-986158 (100 nM) blocked macrophage recruitment to cancer cells by 80% (transwell migration assay) and reduced M2-like macrophage polarization (CD206+ cells) by 65% (flow cytometry) [1] 6. BMS-986158 (1-10 μM) had no cytotoxicity in normal human pancreatic ductal epithelial (HPDE) cells, with cell viability >90% after 72-hour treatment (CCK-8 assay) [1] |
| ln Vivo |
1. In PANC-1 pancreatic cancer xenograft models (female NOD/SCID mice), oral administration of BMS-986158 (5, 15, 30 mg/kg once daily for 21 days) dose-dependently inhibited tumor growth with TGI (tumor growth inhibition) rates of 40%, 68%, and 85% respectively; the 30 mg/kg dose reduced tumor weight by 80% compared to vehicle controls [1]
2. BMS-986158 (15 mg/kg PO) decreased the number of tumor-associated macrophages (TAMs) in xenograft tumors by 70% (immunohistochemistry for CD68) and reduced M2-TAM markers (CD206, Arg1) by 60-65% at the mRNA level (qPCR of tumor tissues) [1] 3. The compound (15 mg/kg PO) reduced serum levels of CCL2 (65%) and CSF1 (70%) in tumor-bearing mice (ELISA), and downregulated intratumoral IL-6 expression by 75% (western blot) [1] 4. In a syngeneic pancreatic cancer model (KPC mice), BMS-986158 (15 mg/kg PO qd for 28 days) inhibited primary tumor growth by 72% and reduced liver metastasis by 60% (bioluminescence imaging) [1] 5. Combination treatment of BMS-986158 (10 mg/kg PO) with anti-PD-1 antibody (200 μg/mouse IP q3d) in PANC-1 xenografts enhanced TGI to 92% (vs. 55% for BMS-986158 alone and 30% for anti-PD-1 alone) and increased intratumoral CD8+ T-cell infiltration by 2.5-fold (flow cytometry) [1] |
| Enzyme Assay |
1. BRD4 bromodomain AlphaScreen binding assay: Recombinant human BRD4 BD1 and BD2 proteins were incubated with biotinylated acetylated histone H4 (H4K5ac/K8ac) peptide, Eu-labeled streptavidin, and serial dilutions of BMS-986158 (0.001-10 μM) in assay buffer (25 mM Tris-HCl, 150 mM NaCl, 0.01% Tween 20, pH 7.4) at 25°C for 60 minutes; AlphaScreen signals (615/520 nm) were measured to quantify the inhibition of BRD4-histone peptide binding, and IC50 values were calculated from dose-response curves using a four-parameter logistic model [1]
2. BET family selectivity assay: Recombinant human BRD2 and BRD3 bromodomain proteins were incubated with the same biotinylated H4 peptide and BMS-986158 (0.01-10 μM) under identical conditions to the BRD4 assay; AlphaScreen signals were measured to determine IC50 values for BRD2 and BRD3, and selectivity ratios relative to BRD4 were calculated [1] 3. Non-BET bromodomain binding assay: Recombinant human BRD7 and BRD9 proteins were incubated with acetylated histone peptides and BMS-986158 (0.1-10 μM) in AlphaScreen assay buffer; signal intensity was measured to assess off-target binding to non-BET bromodomains [1] |
| Cell Assay |
1. Cancer cell proliferation assay: Human pancreatic cancer cells (PANC-1, MiaPaCa-2) and normal HPDE cells were seeded in 96-well plates at 5×10³ cells/well and treated with BMS-986158 (0.01-10 μM) for 72 hours at 37°C with 5% CO₂; CCK-8 reagent was added and incubated for 2 hours, and absorbance was measured at 450 nm to calculate cell viability and IC50 values [1]
2. Cancer cell-macrophage co-culture migration assay: THP-1 monocytes were differentiated into macrophages with PMA (100 nM) for 48 hours; PANC-1 cells were seeded in the lower chamber of transwell plates and treated with BMS-986158 (10-1000 nM) for 24 hours; macrophages were added to the upper chamber, and after 12 hours of incubation, migrated macrophages on the lower surface were fixed, stained with crystal violet, and counted under a microscope [1] 3. Cytokine/chemokine expression qPCR assay: PANC-1 cells were treated with BMS-986158 (10-1000 nM) for 24 hours; total RNA was extracted and reverse-transcribed to cDNA; qPCR was performed with primers for CCL2, CSF1, IL-6, and GAPDH (housekeeping gene); relative gene expression was calculated using the 2^(-ΔΔCt) method [1] 4. Macrophage polarization flow cytometry assay: THP-1-derived macrophages were co-cultured with BMS-986158-treated PANC-1 cells for 48 hours; cells were harvested, stained with anti-CD206-PE and anti-CD86-FITC antibodies, and analyzed by flow cytometry to quantify M2 (CD206+) and M1 (CD86+) macrophage populations [1] 5. BRD4 target gene western blot assay: PANC-1 cells were treated with BMS-986158 (10-1000 nM) for 24 hours; whole-cell lysates were prepared, separated by SDS-PAGE, and probed with antibodies against BRD4, phospho-RNA Pol II (Ser2), c-Myc, and β-actin (loading control); band intensities were quantified by densitometry to assess protein expression changes [1] |
| Animal Protocol |
1. PANC-1 xenograft tumor model: Female NOD/SCID mice (6-8 weeks old) were injected subcutaneously with 5×10⁶ PANC-1 cells into the right flank; when tumors reached 100-150 mm³, mice were randomized into treatment groups; BMS-986158 was formulated in 10% DMSO, 40% PEG400, and 50% sterile saline, and administered orally via gavage at 5, 15, or 30 mg/kg once daily for 21 days (volume: 10 mL/kg); tumor volume was measured every 3 days (volume = length × width² / 2), and mice were euthanized at study end for tumor weight measurement and tissue collection [1]
2. Syngeneic KPC pancreatic cancer model: KPC mice (8-10 weeks old) with spontaneous pancreatic tumors were treated with BMS-986158 (15 mg/kg PO qd) or vehicle for 28 days; tumor growth was monitored by bioluminescence imaging (luciferase-expressing KPC cells) every 7 days, and liver metastasis was assessed by ex vivo bioluminescence imaging at study end [1] 3. Combination therapy with anti-PD-1: PANC-1 xenograft mice were treated with BMS-986158 (10 mg/kg PO qd) and anti-PD-1 antibody (200 μg/mouse IP q3d) for 21 days; control groups received single-agent treatment or vehicle; tumor volume was measured twice weekly, and tumor tissues were collected for flow cytometry analysis of CD8+ T-cell infiltration [1] 4. Tissue and serum analysis protocol: Tumor tissues were homogenized for qPCR and western blot analysis of cytokine/chemokine expression and BRD4 target genes; blood samples were collected by cardiac puncture, and serum was separated for ELISA analysis of CCL2 and CSF1 levels; tumor sections were stained with anti-CD68 antibody for immunohistochemical quantification of TAMs [1] |
| Toxicity/Toxicokinetics |
1. At concentrations up to 10 μM, BMS-986158 did not show significant cytotoxicity to normal human pancreatic ductal epithelial cells (HPDE), with cell viability >90% after 72 hours of treatment [1]. 2. In NOD/SCID mice treated with BMS-986158 (30 mg/kg, once daily, orally for 21 days), no significant changes were observed in body weight (decreased by <5%), food intake, or toxic clinical symptoms (somnia, ruffled fur) [1]. 3. Histopathological examination of the major organs (liver, kidney, spleen, pancreas) of the treated mice revealed no treatment-related lesions or inflammation [1].
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| References | |
| Additional Infomation |
BMS-986158 is being investigated in the clinical trial NCT02419417 (Study of BMS-986158 in specific advanced cancer patients). Ezobresib is an inhibitor of the brominated domain (BRD) and terminal domain (BET) protein family with potential antitumor activity. After administration, ezobresib binds to the acetylated lysine binding site in the BET protein BRD, thereby preventing the interaction between the BET protein and acetylated histones. This disrupts chromatin remodeling and inhibits the expression of certain growth-promoting genes, thus suppressing tumor cell growth. BET proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators that bind to acetylated lysine residues at the tails of histones H3 and H4 and regulate chromatin structure and function; they play important roles in the regulation of gene expression during development and cell growth.
1. BMS-986158 is a potent and selective small molecule BRD4 inhibitor designed to target the tumor microenvironment by blocking the interaction between cancer cells and macrophages[1] 2. The mechanism of action of BMS-986158 includes binding to the bromodomain of BRD4, inhibiting its interaction with acetylated histones, and inhibiting the transcription of pro-inflammatory cytokines/chemokines (CCL2, CSF1, IL-6), which can recruit and polarize tumor-associated macrophages (TAMs)[1] 3. BMS-986158 exhibits synergistic antitumor activity with immune checkpoint inhibitors (anti-PD-1) by reprogramming the tumor microenvironment and enhancing CD8+ T cell function. Infiltration[1] 4. Preclinical data suggest that BMS-986158 is effective in pancreatic cancer models and may be applicable to other solid tumors characterized by high BRD4 expression and TAM invasion (e.g., breast cancer, lung cancer)[1] |
| Molecular Formula |
C30H33N5O2
|
|---|---|
| Molecular Weight |
495.61532664299
|
| Exact Mass |
495.263
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| CAS # |
1800340-40-2
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| PubChem CID |
118196485
|
| Appearance |
White to off-white solid powder
|
| LogP |
4.1
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
37
|
| Complexity |
769
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
OC(C)(C)C1=CC=C2C(N([C@H](C3=CC=CC=C3)C4CCOCC4)C5=C2N=CC(C6=C(C)N=NN6C)=C5)=C1
|
| InChi Key |
KGERZPVQIRYWRK-GDLZYMKVSA-N
|
| InChi Code |
InChI=1S/C30H33N5O2/c1-19-28(34(4)33-32-19)22-16-26-27(31-18-22)24-11-10-23(30(2,3)36)17-25(24)35(26)29(20-8-6-5-7-9-20)21-12-14-37-15-13-21/h5-11,16-18,21,29,36H,12-15H2,1-4H3/t29-/m1/s1
|
| Chemical Name |
(S)-2-(3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indol-7-yl)propan-2-ol
|
| Synonyms |
BMS-986158; BMS 986158; BMS986158
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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)
|
| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~100.88 mM)
H2O : < 0.1 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.04 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.04 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. 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.04 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0177 mL | 10.0884 mL | 20.1767 mL | |
| 5 mM | 0.4035 mL | 2.0177 mL | 4.0353 mL | |
| 10 mM | 0.2018 mL | 1.0088 mL | 2.0177 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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