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Bcl-2 phase I candidate2019-04-30T09:20:33+01:00

Project Description

B-cell lymphoma 2 (Bcl-2) – phase I clinical candidate

Casara et al. Oncotarget 2018

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 leukaemia. Thus, Bcl-2 has become an attractive target for therapeutic intervention in cancer.

A novel, orally bioavailable, Bcl-2 selective and potent inhibitor called S55746 (also known as BCL201), which occupies the hydrophobic groove of Bcl-2, was obtained.

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X-ray crystal structure of S55746 in complex with Bcl-2 (PDB: 6GL8)

The selectivity profile of S55746 demonstrates no significant binding to Mcl-1, BFL-1 (Bcl-2A1/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 haematological 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 leukaemia and mantle cell lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumour efficacy in two haematological xenograft models with no weight loss and no change in behaviour. Taken together, these data demonstrate that S55746 is a novel, well-tolerated BH3-mimetic targeting selectively and potently the Bcl-2 protein.

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