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S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth

Geneste , Olivier and Clapéron, Audrey and Colland, Frédéric and Kraus-Berthier, Laurence and Le Toumelin-Braizat, Gaëtane and Studeny, Aurélie and Guasconi, Ghislaine and Bruno, Alain and Chanrion, Maia and Lysiak-Auvity, Gaelle and Girard, Anne-Marie and Schneider, Emilie and Gravé, Fabienne and Casara, Patrick and Le Diguarher, Thierry and Starck, Jérome-Benoit and Henlin, Jean-Michel and Murray, James and Davidson, James and Chen, Ijen and Whitehead, Neil and Graham, Christopher and Matassova, Natalia and Dokurno, Pawel and Pedder, Christopher and Hubbard, Roderick and Wood, Mike and Morris, Erick and Wang, Youzhen and Qiu, Shumei and Amiot, Martine and Maïga, Sophie and Le Gouill, Steven and Vogler, Meike and Cohen, Gerry M and Dyer, Martin JS and Rocchetti, Franscesca and Hickman, John A. (2018) S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth. Oncotarget, 9 (28). pp. 20075-20088. ISSN 19492553


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.

Item Type: Article
Keywords: Apoptosis BCL-2 BH3-mimetics Hematological malignancies Inhibitor
Date Deposited: 08 May 2018 00:45
Last Modified: 25 Jan 2019 00:45


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