Development of first-in-class small molecule inhibitors of FLIP which activate caspase-8, the nodal regulator of apoptosis, necroptosis and pyroptosis

Abstract:

Caspase-8 is the initiator caspase for the extrinsic apoptotic pathway and now recognized as the molecular “switch” that controls 3 major forms of programmed cell death: apoptosis, necroptosis and pyroptosis. As such, methods to selectively activate caspase-8 in appropriate disease contexts represent an exciting new therapeutic paradigm. In cancer, evasion of cell death is a fundamental cause of resistance to therapy, prompting the development of therapeutics that reactivate cell death pathways, with the first of these (targeting the intrinsic apoptotic pathway) recently clinically approved. The apoptosis modulator FLIP is a non-redundant inhibitor of caspase-8 activation in the extrinsic apoptotic pathway and is the only human pseudo-caspase. FLIP is frequently overexpressed in a number of cancers and leukemias and, through its modulation of caspase-8, has been shown to be a major mediator of resistance to …

Año de publicación:

2020

Keywords:

Fuente:

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