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. Venetoclax (Venclexta™), a selective BCL-2 inhibitor, is the first member of a new class of anti-cancer drugs, called BH3 mimetics, to be approved for CLL and AML. Here, we describe the identification of a novel potent and selective BCL-2 inhibitor named S65487/VOB560 that has a different binding mode on BCL-2 compared to Venetoclax. This inhibitor binds to the BH3 hydrophobic groove of BCL-2. Its selectivity profile demonstrates lack of significant binding to MCL-1, BFL-1 and poor affinity for BCL-XL. S65487/VOB560 induces apoptosis in a panel of hematological cancer cell lines and inhibits cell proliferation with IC50s in the low nM range. S65487/VOB560 induces complete regression in BCL-2-dependent RS4;11 tumors in vivo after a single IV (intravenous) administration. Strong and persistent tumor regression in xenograft models of lymphoid malignancies in mouse and rat were observed at well tolerated doses following weekly IV administration of S65487 in combination with the MCL-1-specific inhibitor, S64315/MIK665. These positive findings were further confirmed in a panel of AML PDX tumor models. Recently, acquired BCL-2 mutations (such as G101V and D103Y) were identified in patients with Chronic Lymphocytic Leukemia becoming resistant to Venetoclax. Interestingly, S65487/VOB560 is active on such BCL-2 mutants and induces apoptosis in preclinical resistance models. Altogether, these data demonstrate that S65487/VOB560 has significant therapeutic potential against human lymphoid and myeloid malignancies as well as in patients with Venetoclax resistant leukemias. Clinical studies are currently ongoing with S65487/VOB560 (NCT03755154).

Citation Format: Arnaud Le Tiran, Audrey Claperon, James Davidson, Jérôme-Benoit Starck, Thierry Le Diguarher, Maïa Chanrion, Prakash Mistry, Youzhen Wang, Elodie Monceau, Fabienne Bernhardt, Francesca Rocchetti, Gaelle Lysiak-Auvity, Ijen Chen, Zoe Daniels, Chris Pedder, Mandy Fallowfield, Jean-Michel Henlin, Imre Fejes, Janos Tatai, Miklos Nyerges, Didier Durand, Marion Zarka, Sneha Sanghavi, Anne-Marie Girard, Marie Schoumacher, Laurence Kraus-Berthier, Rick Newcombe, Ensar Halilovic, Sébastien Banquet, Alain Rupin, Heiko Maacke, James Murray, Erick Morris, Francesco Hofmann, Frédéric Colland, Olivier Geneste. Identification of S65487/VOB560 as a potent and selective intravenous 2nd-generation BCL-2 inhibitor active in wild-type and clinical mutants resistant to Venetoclax [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1276.