Ensemble Therapeutics has utilized its proprietary DNA-Programed Chemistry (DPC) platform for synthesis and screening of combinatorial macrocyclic libraries against a wide variety of protein-protein interaction (PPI) targets. Employing this platform, we have been able to find multiple hits and SAR information for numerous PPI targets. Despite being outside conventional small molecule Ro5 space, the macrocycles can be drug-like with properties including cell membrane penetration and oral bioavailability. Through library screening and medicinal chemistry effort we have developed several series of macrocyclic inhibitors of the BIR2 and BIR3 domains of XIAP. Inhibiting the sequestration of pro-apoptotic caspases by BIR2 and BIR3 induces apoptosis selectively in cancer cell lines. After optimization for drug like ADME properties these macrocyclic inhibitors have shown efficacy in in vitro and in vivo models.

Screening, synthesis, and development of macrocyclic XIAP antagonists with drug like properties

248th National Meeting (2014)

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