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Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion. Here, we describe a novel orally bioavailable BCL-2 selective and potent inhibitor called S55746 (also known as BCL201). S55746 occupies the hydrophobic groove of BCL-2. Its selectivity profile demonstrates no significant binding to MCL-1, BFL-1 (BCL2A1/A1) and poor affinity for BCL-XL. Accordingly, S55746 has no cytotoxic activity on BCL-XL-dependent cells, such as platelets. In a panel of hematological cell lines, S55746 induces hallmarks of apoptosis including externalization of phosphatidylserine, caspase-3 activation and PARP cleavage. Ex vivo , S55746 induces apoptosis in the low nanomolar range in primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior. Taken together, these data demonstrate that S55746 is a novel, well-tolerated BH3-mimetic targeting selectively and potently the BCL-2 protein., Competing Interests: CONFLICTS OF INTEREST P Casara and JA Hickman are former employees of Institut de Recherches Servier. M Chanrion, A Claperon, F Colland, O Geneste, AM Girard, F Gravé, G Guasconi, JM Henlin, G Le Toumelin-Braizat, G Lysiak-Auvity, F Rocchetti, E Schneider, JB Starck and A Studeny are full-time employees of Institut de Recherches Servier. T Le Diguarher is a full-time employee of Technology Servier. A Bruno and L Kraus-Berthier are full-time employees of Institut de Recherches Internationales Servier. E Morris, S Qiu and Y Wang are full-time employees of Novartis Institutes for BioMedical Research; E Morris and Y Wang are stock owner of Novartis. S LeGouill has served on advisory board for Servier. Amiot and Cohen's laboratories have received research funds from Servier. I Chen, J Davidson, P Dokurno, C Graham, N Matassova, J Murray, C Pedder, N Whitehead, M Wood are full-time employees of Vernalis Ltd. R Hubbard is a part-time employee of Vernalis Ltd.

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.