Abstract
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.
Highlights
Apoptosis is a tightly controlled and evolutionarily conserved process of programmed cell death that is crucial for tissue homeostasis [1]
Fluorescence polarization (FP) data, using Fluorescent-PUMA as a binder, demonstrates that S55746 is a potent inhibitor of B-cell Lymphoma 2 (BCL-2) (Ki = 1.3 nM)
We describe S55746, a novel bona fide BH3 mimetic compound which selectively inhibits BCL-2
Summary
Apoptosis is a tightly controlled and evolutionarily conserved process of programmed cell death that is crucial for tissue homeostasis [1]. BCL-2 family proteins are crucial regulators of the mitochondrial apoptotic pathway and are characterized by the presence of up to four conserved BCL-2 Homology (BH) domains. BCL-2 family proteins are divided into 3 functionally distinct groups: (i) the pro-survival proteins (BCL-2, BCL-XL, BCL-W, MCL-1 and BFL-1/BCL2A1/A1), (ii) the multi-BH domain cell death effectors (BAX, BAK, BOK) and (iii) the BH3-only apoptosis initiators (e.g. BIM, BAD, NOXA) [5]. Dynamic interactions between members of BCL-2 family subgroups, involving binding of the BH3 domain of the pro-apoptotic members to a groove at the surface of the pro-survival proteins, control commitment to apoptosis [7]. Following activation by cellular stress, BH3-only proteins initiate apoptosis by inhibiting the pro-survival BCL-2 proteins [8] and potentially by directly activating BAX and BAK [9]. The subsequent activation and oligomerization of the death effectors BAX and BAK result in mitochondrial outer membrane permeabilization and apoptosis
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