S63845 specifically binds with high affinity to the BH3-binding groove of MCL1. S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway.
S63845 is a highly selective and potent MCL-1 with Kd value of 0.19nM with no discernible binding to the other BCL-2 members, BCL-2 or BCL-X and exhibited little toxicity in vivo[1]. The extremely low toxicity of S63845 compared with other BCL inhibitors may due to no affinity of S63845 to necessary functions of MCL-1 that go beyond the BH3 domain binding, anti-apoptotic functions that are inhibited by other BH3 mimetics[2]. S63845 kills H929 tumour cell lines by inducing BAX/BAK-dependent apoptosis and dose-dependently induced MCL1 protein levels in HCT-116 cells at concentration ranging in 1-300nM. S63845 exhibited MCL1-dependent anti-proliferative efficiency on haematological cancer-derived cell lines both in vitro and in vivo. Intravenously injection with S63845 at dose of 6.25, 12.5 and 25mg/kg could inhibited tumor growth in a dose-dependent manner in AMO1 multiple myeloma xenograft model and robustly improved the survival of C57BL/6–LY5.1 mice transplanted with Eμ-Myc lymphoma cells at dose of 25mg/kg. S63845 is effective against AML samples in vitro (IC50<1μM) and in vivo (dose at 12.5 and 25mg/kg), but does not readily kill normal human CD34+ donor haematopoietic progenitor cells[1]. S63845 (25 mg/kg intravenously once weekly for 6 weeks, on days 2, 9, 16, 23, 30, and 37) displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified PDX models[3].
作用机制
S63845 specifically binds with high affinity to the BH3-binding groove of MCL1.[1]
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