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.