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

// Patrick Casara 1, * , James Davidson 2, * , Audrey Claperon 3, * , Gaetane Le Toumelin-Braizat 3 , Meike Vogler 4 , Alain Bruno 5 , Maia Chanrion 3 , Gaelle Lysiak-Auvity 3 , Thierry Le Diguarher 1 , Jerome-Benoit Starck 1 , Ijen Chen 2 , Neil Whitehead 2 , Christopher Graham 2 , Natalia Matassova 2 , Pawel Dokurno 2 , Christopher Pedder 2 , Youzhen Wang 6 , Shumei Qiu 6 , Anne-Marie Girard 3 , Emilie Schneider 3 , Fabienne Grave 3 , Aurelie Studeny 3 , Ghislaine Guasconi 3 , Francesca Rocchetti 3 , Sophie Maiga 7 , Jean-Michel Henlin 1 , Frederic Colland 3 , Laurence Kraus-Berthier 5 , Steven Le Gouill 7 , Martin J.S. Dyer 8 , Roderick Hubbard 2 , Mike Wood 2 , Martine Amiot 7 , Gerald M Cohen 9 , John A. Hickman 3 , Erick Morris 6 , James Murray 2 and Olivier Geneste 3 1 Institut de Recherches Servier Discovery Chemistry Unit, Croissy Sur Seine, France 2 Vernalis (RD inhibitor; BH3-mimetics; apoptosis; hematological malignancies Received: September 12, 2017 Accepted: February 26, 2018 Published: April 13, 2018 ABSTRACT Escape from apoptosis is one of the major hallmarksof cancercells. 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 Leukemiawith 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 Leukemiaand Mantle Cell Lymphomapatient 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.