Abstract LB-037: Development and preclinical assessment of a first-in-class small molecule inhibitor of the major cell death regulator protein FLIP

Abstract:

Background Evasion of cell death is a major cause of resistance to cancer therapy, making proteins that regulate cell death clinically-relevant therapeutic targets. The anti-apoptotic protein FLIP is frequently overexpressed in a number of cancers and has been shown by us and others to be a major mediator of drug resistance. FLIP and procaspase-8 form complexes with the adaptor protein FADD in response to a variety of clinically-relevant stimuli, including: ligation of death receptors, such as TRAIL-R1 and R2; and cytotoxic chemotherapeutics. In these complexes, FLIP modulates the activation of procaspase-8, and thereby apoptosis and necroptosis - two major cell death mechanisms. We recently reported that there are important differences between FLIP and procaspase-8 in terms of both their binding affinities and preferred modes of interaction with FADD that are potentially therapeutically exploitable [1]. We …

Año de publicación:

2015

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Fuente:

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