Evasion of apoptosis is one of the fundamental hallmarks of most and perhaps all types of cancer. Targeting anti-apoptotic Bcl-2 family proteins which are key apoptotic regulators in the mitochondrial apoptotic pathway with a goal to overcome apoptosis resistance of tumor cells is a promising cancer therapeutic strategy. Starting from the crystal structure of a lead compound which functions as effective antagonist of Bcl-2 and Bcl-XL in cell-free functional assays in complex with Bcl-XL, integrating a computational structure-based design strategy, we have successfully designed and synthesized potent small-molecule inhibitors of Bcl-2 and Bcl-XL proteins. The most promising compound which was identified in this study binds to Bcl-2 and Bcl-XL with the Ki values <1 nM and shows potent activity in cell growth inhibition in multiple cancer cell lines. Most importantly, this compound strongly induces apoptosis and was capable of achieving complete and long-lasting tumor regression in H146 xenograft tumors. Herein we describe the design, synthesis and in vtro/vivo evaluations of this compound.

Structure-based design, synthesis and evaluation of a potent, dual inhibitors of Bcl-2 and Bcl- X<sub>L</sub> with in vivo activity

243rd National Meeting (2012)

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Structure-based design, synthesis and evaluation of a potent, dual inhibitors of Bcl-2 and Bcl- XL with in vivo activity

Structure-based design, synthesis and evaluation of a potent, dual inhibitors of Bcl-2 and Bcl- X_L with in vivo activity