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.

Combining the selective targeting of tumor cells through antigen-directed recognition and potent cell-killing by cytotoxic payloads, antibody-drug conjugates (ADCs) have emerged in recent years as an efficient therapeutic approach for the treatment of various cancers. Besides a number of approved drugs already on the market, there is a formidable follow-up of ADC candidates in clinical development. While selection of the appropriate antibody (A) and drug payload (D) is dictated by the pharmacology of the targeted disease, one has a broader choice of the conjugating linker (C). In the present paper, we review the chemistry of ADCs with a particular emphasis on the medicinal chemistry perspective, focusing on the chemical methods that enable the efficient assembly of the ADC from its three components and the controlled release of the drug payload.

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.

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