Solid tumors typically contain regions that are hypoxic (reduced oxygen concentration) where cancer cells proliferate. They do this by up-regulating certain genes via specific transcriptional regulators, including HIF2a. Under normoxic conditions (normal oxygen concentration), HIF2a is oxidatively deactivated. An emerging class of potential drugs functions by inhibiting HIF2a, thereby stopping cancer cells from proliferating. Such drugs offer the potential to affect only hypoxic cancer cells while having no effect on normoxic cells. To strengthen validation of this target, we demonstrate by siRNA knockdown that disruption of the regulatory complex leads to halting of protein expression in hypoxic cells without affecting normoxic cells. For lead generation, we (1) developed a computational screening model and validated its ability to correctly discriminate between leads and decoys, (2) computationally screened a virtual library of 5 million commercial compounds, and (3) employed Muse's iterative genetic algorithm to score ligand-receptor interactions, propose synthetic pathways, and optimize physicochemical properties. The most drug-like hits were evolved through computational analysis and synthetic optimization. Through these efforts, we have identified novel families of inhibitors across 6 different chemotypes. Binding of these compounds has been demonstrated in an alpha-screen based assay and functional activity has been demonstrated in a VEGF suppression assay. We show that selected representatives from the 6 leading chemotypes are among the most potent inhibitors yet described for this target.

Identification of inhibitors of HIF2a as modulators of the hypoxia response for the treatment of cancer

251st National Meeting (2016)

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