Development and preclinical evaluation of unique first-in-class small molecule inhibitors of the anti-apoptotic protein FLIP

Abstract:

In cancer, evasion of cell death is a fundamental cause of resistance to therapy, prompting the development of therapeutics that reactivate cell death pathways such as Bcl-2 family inhibitors and IAP antagonists. The apoptosis modulator Cellular FLICE-like inhibitory protein (FLIP) is a non-redundant inhibitor of caspase-8 activation and is the only human pseudo-caspase. Caspase-8 is the initiator caspase for the extrinsic apoptotic pathway and is now recognized as the molecular “switch” that controls the 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. FLIP is frequently overexpressed in solid and haematological cancers where it is associated with poor prognosis and chemo- and radio-resistance. Moreover, by regulating caspase-8 activity, FLIP is a …

Año de publicación:

2021

Keywords:

Fuente:

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