BMS-986158
目录号 : GC32812A BET bromodomain inhibitor
Cas No.:1800340-40-2
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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BMS 986158 is a BET bromodomain inhibitor with anticancer activity.1 It decreases c-Myc expression and induces cancer cell death in c-Myc-driven cancer cell lines in vitro. BMS 986158 inhibits tumor growth in triple-negative breast, colorectal, and lung cancer patient-derived mouse xenograft models.
1.Gavai, A.V., Norris, D., Tortolani, D., et al.Abstract 5789: Discovery of clinical candidate BMS-986158, an oral BET inhibitor, for the treatment of cancerCancer Res.78(13 Supplement)5789-5789(2018)
Cas No. | 1800340-40-2 | SDF | |
Canonical 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 | ||
分子式 | C30H33N5O2 | 分子量 | 495.62 |
溶解度 | DMSO : 1 mg/mL (2.02 mM) | 储存条件 | Store at -20°C |
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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 |
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Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction
Nat Commun 2020 Apr 14;11(1):1833.PMID:32286255DOI:10.1038/s41467-020-15290-0.
Small molecule inhibitor of the bromodomain and extraterminal domain (BET) family proteins is a promising option for cancer treatment. However, current BET inhibitors are limited by their potency or oral bioavailability. Here we report the discovery and characterization of NHWD-870, a BET inhibitor that is more potent than three major clinical stage BET inhibitors BMS-986158, OTX-015, and GSK-525762. NHWD-870 causes tumor shrinkage or significantly suppresses tumor growth in nine xenograft or syngeneic models. In addition to its ability to downregulate c-MYC and directly inhibit tumor cell proliferation, NHWD-870 blocks the proliferation of tumor associated macrophages (TAMs) through multiple mechanisms, partly by reducing the expression and secretion of macrophage colony-stimulating factor CSF1 by tumor cells. NHWD-870 inhibits CSF1 expression through suppressing BRD4 and its target HIF1α. Taken together, these results reveal a mechanism by which BRD4 inhibition suppresses tumor growth, and support further development of NHWD-870 to treat solid tumors.
BMS-986158, a Small Molecule Inhibitor of the Bromodomain and Extraterminal Domain Proteins, in Patients with Selected Advanced Solid Tumors: Results from a Phase 1/2a Trial
Cancers (Basel) 2022 Aug 23;14(17):4079.PMID:36077617DOI:10.3390/cancers14174079.
This phase 1/2a, open-label study (NCT02419417) evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-986158, a selective bromodomain and extraterminal domain (BET) inhibitor. Dose escalation was performed with 3 BMS-986158 dosing schedules: A (5 days on, 2 days off; range, 0.75-4.5 mg), B (14 days on, 7 days off; 2.0-3.0 mg), and C (7 days on, 14 days off; 2.0-4.5 mg). Eighty-three patients were enrolled and received ≥1 BMS-986158 dose. Diarrhea (43%) and thrombocytopenia (39%) were the most common treatment-related adverse events (TRAEs). A lower incidence of TRAEs was found with schedules A (72%) and C (72%) vs. B (100%). Stable disease was achieved in 12 (26.1%), 3 (37.5%), and 9 (31.0%) patients on schedules A, B, and C, respectively. Two patients on schedule A with a 4.5-mg starting dose (ovarian cancer, n = 1; nuclear protein in testis [NUT] carcinoma, n = 1) experienced a partial response. BMS-986158 demonstrated rapid-to-moderate absorption (median time to maximum observed plasma concentration, 1-4 h). As expected with an epigenetic modifier, expression changes in select BET-regulated genes occurred with BMS-986158 treatment. Schedule A dosing (5 days on, 2 days off) yielded tolerable safety, preliminary antitumor activity, and a dose-proportional PK profile.
Bromodomain and Extra-Terminal Inhibitor BMS-986158 Reverses Latent HIV-1 Infection In Vitro and Ex Vivo by Increasing CDK9 Phosphorylation and Recruitment
Pharmaceuticals (Basel) 2022 Mar 10;15(3):338.PMID:35337136DOI:10.3390/ph15030338.
Latent reservoir persistence remains a major obstacle for curing human immunodeficiency virus type 1 (HIV-1) infection. Thus, strategies for the elimination of latent HIV-1 are urgently needed. As a bromodomain and extra-terminal (BET) inhibitor, BMS-986158 has been used in clinical trials for advanced solid tumors and hematological malignancies. Here, we found that BMS-986158 reactivated latent HIV-1 in three types of HIV-1 latency cells in vitro, and in combination antiretroviral therapy (cART)-treated patient-derived peripheral blood mononuclear cells ex vivo, without influencing global immune cell activation. BMS-986158 reactivated latent HIV-1 by increasing phosphorylation of CDK9 at Thr186 and promoting recruitment of CDK9 and RNA polymerase II to the HIV-1 long terminal repeat in J-Lat cells. Furthermore, BMS-986158 exerted strong synergism in reactivating latent HIV-1 when combined with prostratin and vorinostat and enhanced the antiviral activity of anti-HIV-1 drugs. Finally, BMS-986158 showed antiviral activity in an HIV-1 acute infection model, possibly by arresting the cell cycle in infected cells. Thus, these results suggest that BMS-986158 is a potential candidate for AIDS/HIV-1 therapy.
Safety and Efficacy of Bromodomain and Extra-Terminal Inhibitors for the Treatment of Hematological Malignancies and Solid Tumors: A Systematic Study of Clinical Trials
Front Pharmacol 2021 Jan 26;11:621093.PMID:33574760DOI:10.3389/fphar.2020.621093.
Background: The upregulated expression of BET proteins is closely associated with the occurrence and development of hematological malignancies and solid tumors. Several BET inhibitors have been developed, and some have been in phase I/II of clinical trials. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated. Methods: We retrieved and reviewed published reports on the clinical trials of twelve BET inhibitors including AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762, OTX-015, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207 for patients with hematological malignancies and solid tumors and summarized their published target genes. Results: In the monotherapy of BET inhibitors, the most common and severe (grade ≥3) hematological adverse events (AEs) are thrombocytopenia, anemia, and neutropenia. The most common non-hematological syndromes are diarrhea, nausea, fatigue, dysgeusia, and decreased appetite, while the most severe AE is pneumonia. Additionally, T max of these BET inhibitors was between 0.5-6 h, but the range for T 1/2 varied significantly. According to published data, the rates of SD, PD, CR and PR were 27.4%, 37.6%, 3.5%, and 5.7%, respectively, which is not very satisfactory. In addition to BRD4, oncogene MYC is another common target gene of these BET inhibitors. Ninety-seven signaling pathways may be regulated by BET inhibitors. Conclusion: All BET inhibitors reviewed in our study exhibited exposure-dependent thrombocytopenia, which may limit their clinical application. Moreover, further efforts are necessary to explore the optimal dosing schemes and combinations to maximize the efficacy of BET inhibitors.
Bromodomain and extra-terminal inhibitors-A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children-ACCELERATE
Eur J Cancer 2021 Mar;146:115-124.PMID:33601323DOI:10.1016/j.ejca.2021.01.018.
Based on biology and pre-clinical data, bromodomain and extra-terminal (BET) inhibitors have at least three potential roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas, MYC/MYCN-driven cancers and fusion-driven malignancies. However, there are now at least 10 BET inhibitors in development, with a limited relevant paediatric population in which to evaluate these medicinal products. Therefore, a meeting was convened with the specific aim to develop a consensus among relevant biopharmaceutical companies, academic researchers, as well as patient and family advocates, about the development of BET inhibitors, including prioritisation and their specific roles in children. Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study (BMS-986158) only opened in 2019. In the future, when there is strong mechanistic rationale or pre-clinical activity of a class of medicinal product in paediatrics, early clinical evaluation with embedded correlative studies of a member of the class should be prioritised and rapidly executed in paediatric populations. There is a strong mechanistic and biological rationale to evaluate BET inhibitors in paediatrics, underpinned by substantial, but not universal, pre-clinical data. However, most pan-BET inhibitors have been challenging to administer in adults, since monotherapy results in only modest anti-tumour activity and provides a narrow therapeutic index due to thrombocytopenia. It was concluded that it is neither scientifically justified nor feasible to undertake simultaneously early clinical trials in paediatrics of all pan-BET inhibitors. However, there is a clinical need for global access to BET inhibitors for patients with NUT carcinoma, a very rare malignancy driven by bromodomain fusions, with proof of concept of clinical benefit in a subset of patients treated with BET inhibitors. Development and regulatory pathway in this indication should include children and adolescents as well as adults. Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous system-penetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation. This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer.