Development and pre-clinical assessment of a first-in-class small molecule inhibitor of FLIP

Abstract:

Evasion of cell death is a major cause of resistance to anti-cancer therapies, making proteins that regulate cell death clinically relevant therapeutic targets. The anti-apoptotic protein FLIP is frequently overexpressed in a number of cancers and leukemias and has been shown to be a major mediator of resistance to chemo- and radio-therapies and to cell death induced by immune effector cells. 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 treatment with chemotherapeutic agents. In these complexes, FLIP modulates the activation of procaspase-8, and thereby regulates induction of apoptosis and necroptosis - two major cell death mechanisms. Herein, we report the development and pre-clinical characterization of first-in-class inhibitors of FLIP. Molecular modelling …

Año de publicación:

2019

Keywords:

Fuente:

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