Will the BET workout in Oncology? an overview of BET inhibitors

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Will the BET workout in Oncology? an overview of BET inhibitors


Will the BET workout in Oncology? an overview of BET inhibitors

The bromodomain and extra-terminal (BET) subfamily of bromodomain-containing proteins has emerged in the last few years as an exciting, novel target group in oncology. BET inhibitors are a class of drugs used in research with anti-cancer and immunosuppressive effects. These molecules reversibly bind the bromodomains of BET proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones and transcription factors. BET inhibitors showed promising antitumor efficacy in a number of preclinical cancer models and led to clinical studies focusing on the treatment of solid tumors and hematological malignancies. Recent studies showed that BET inhibitors can be instrumental in overcoming resistance to other targeted therapies when used in combination therapies. Major BET inhibitors include GSK1210151A, MK-8628, TEN-010, BI-894999, CPI-203, GS-5829, INCB-54329, BMS-986158 and RVX-208.

MK-8628 (Merck): MK-8628 (OTX015) is a small molecule that specifically binds to BRDs 2, 3 and 4, thereby inhibiting binding to acetylated histones, resulting in downregulation of several oncogenes. Sequential combinations of MK-8628 with other epigenetic modifying drugs, panobinostat and azacitidine have shown a synergic effect on growth of the leukemia cell lines, supporting MK-8628 evaluation in a clinical trials in relapsed/refractory leukemia patients. Results presented in ASCO-16 showed that administration of MK-8628 was found to be safe and well tolerated in patients with recurrent brain cancer. The MTD was established at 120 mg MK-8628 QD with PK indicating that MK-8628 had reached biologically active levels. MK-8628 also exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations and exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus.

BI-894999 (Boehringer): BI 894999 is a highly potent and selective orally available BET inhibitor. BI 894999 displayed strong anti-proliferative activity, particularly in hematological cell lines. Potent tumor growth inhibition was demonstrated in xenograft models of AML and lymphoma as a monotherapy, and combinatorial activity was observed in a range of distinct combination settings. Combination therapy of BI-894999 with a BTK inhibitor led to tumor regression in 6/7 animals in a lymphoma model. In vivo potency of BI-894999 in SCLC, prostate and pancreas tumor models suggested the potential of this BET inhibitor for treatment of solid cancers. Results from phase I clinical trial on 28 patients, to be presented at ASCO-17 demonstrated that, BI-894999 showed target engagement at doses ≥1 mg and demonstrated clinical activity, with 1.5mg as the MTD. The most frequent (≥10%) treatment-related adverse events were: fatigue (50%), thrombocytopenia (29%), decreased appetite (21%), diarrhea (18%), increased troponin T (18%), dysgeusia (14%), nausea (14%), stomatitis (14%), increased CK (11%), neutropenia (11%) and vomiting (11%). The combination of the BI 894999 with CDK9 inhibition also suggests a promising regimen for the treatment of leukemia.

GSK525762 (GlaxoSmithKline): GSK1210151A (I-BET151) is a novel selective inhibitor of the bromodomain and extra terminal (BET) family proteins BRD2, BRD3, and BRD4. It is a pan-BET inhibitor showing strong synergistic activity with fulvestrant in killing ER+BC cells in vitro and in xenograft models. Inhibition of BRD4 by the small molecule inhibitor GSK1210151A resulted in a reduced RacPyV genome within cells in vitro, as well as significant reduction of viral gene transcripts LT and VP1, highlighting its importance in both maintenance of the viral genome and in driving oncogenic transformation by RacPyV. A phase I/II dose escalation and expansion study is under planning to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with fulvestrant in subjects with ER+ breast cancer, the data to be presented in ASCO-17.

GS-5829 (Gilead): GS-5829 is an orally bioavailable inhibitor of the Bromodomain and Extra-Terminal (BET) family of proteins, which binds to the acetylated lysine recognition motifs in the bromodomains of BET proteins, thereby preventing the interaction between the BET proteins and acetylated histones. Currently, GS-5829 is in phase I/II clinical trials for the treatment of advanced prostate cancer and Advanced Estrogen Receptor Positive HER2- Breast Cancer, along with a phase I clinical trials for the treatment of advanced solid tumours and diffuse large B-cell lymphomas. Data suggested that combination of GS-4059 and GS-5829 (BTK inhibitor) have increased activity in patients with the ABC subtype of DLBCL and Reduces Expression of MYC, IL-10, and IL-6 in Vitro.

The initial success of BET inhibitor development, resulted in rapid clinical translation. Currently, multiple clinical trials that are in various phases of development seek to target BET proteins in haematological and solid tumours. It remains to be seen whether and how BET inhibition will apply to the treatment of tumor types as a monotherapy and as combination strategy with other drugs. In the future, it will also be interesting to see whether resistance to BET inhibition can also be alleviated or prevented by combination treatments.


By Dr. Rupesh Tyagi
Senior Research Analyst, Science and Research @ Innoplexus

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