1. S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth
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Patrick Casara, James Davidson, Audrey Claperon, Gaëtane Le Toumelin-Braizat, Meike Vogler, Alain Bruno, Maïa Chanrion, Gaëlle Lysiak-Auvity, Thierry Le Diguarher, Jérôme-Benoît Starck, Ijen Chen, Neil Whitehead, Christopher Graham, Natalia Matassova, Pawel Dokurno, Christopher Pedder, Youzhen Wang, Shumei Qiu, Anne-Marie Girard, Emilie Schneider, Fabienne Gravé, Aurélie Studeny, Ghislaine Guasconi, Francesca Rocchetti, Sophie Maïga, Jean-Michel Henlin, Frédéric Colland, Laurence Kraus-Berthier, Steven Le Gouill, Martin J.S. Dyer, Roderick Hubbard, Mike Wood, Martine Amiot, Gerald M Cohen, John A. Hickman, Erick Morris, James Murray, Olivier Geneste, Institut de Recherches Servier, Vernalis (R&D) Ltd, Institute for Experimental Cancer Research in Pediatrics, Goethe-Universität Frankfurt am Main, Institut de Recherches Internationales Servier [Suresnes] (IRIS), Novartis Institute of Biomedical Research, Oncology Drug Discovery, Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Ernest and Helen Scott Haematological Research Institute, University of Leicester, Institute of Translational Medicine, University of Liverpool, Goethe-University Frankfurt, Institut de Recherches Internationales Servier [Suresnes] ( IRIS ), Regulation of Bcl2 and p53 networks in Multiple Myeloma and Mantle Cell Lymphoma ( CRCINA - Département NOHMAD - Equipe 10 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
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0301 basic medicine ,apoptosis ,BCL-2 ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,BH3-mimetics ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,3. Good health ,inhibitor ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Oncology ,030220 oncology & carcinogenesis ,hematological malignancies ,Research Paper - Abstract
International audience; 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, welltolerated BH3-mimetic targeting selectively and potently the BCL-2 protein.
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- 2018
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