The talk will cover some themes of drug discovery through several programs that advanced to advanced clinical development and to approval. The focus will be on the design and characterization of axitinib and key published clinical results to date. The data demonstrates that axitinib is differentiated in the class of VEGFR tyrosine kinase inhibitors (VEGFR TKIs). The class collectively has changed the landscape of how cancer is treated, particularly in renal cell carcinoma (RCC). The drug discovery team solved the first Xray structure of VEGFR2 kinase, and leveraged a computer-aided 3D molecular design platform of optimization, which was updated iteratively with structures of the inhibitor prototypes bound to the target VEGFR2 kinase. Principles of modern drug design, focused on potency-efficiency, were employed to achieve remarkable levels of potency against the target kinase, while also achieving selectivity across the 500+ members of the large kinase gene family of proteins. A number of key assays, with isolated protein and in whole cells, were required to inform the discovery effort, and help solve some big challenges and mysteries during the discovery effort. To fully understand the potency-efficiency of the best designs, crystallography relied on newly prepared constructs of protein, inclusive of the important juxtamembrane (JM) domain. Collectively, the studies elucidate unique drug-kinase interactions for axitinib that are dependent on distinct JM-domain conformations, resulting in significant potency and ligand-efficiency differences in the class. The identified structural trends are consistent with <i>in vitro</i>measurements, which also translate well to clinical performance in the class that clearly differentiates axitinib from other members. Additional oncology programs will be highlighted briefly to illustrate or support key lessons in modern medicinal chemistry.

<b>Award Address</b> (ACS Award for Creative Invention sponsored by the ACS Corporation Associates). Design of kinase inhibitor medicines utilizing protein-ligand structures and property-based efficiency

256th National Meeting (2018)

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Award Address (ACS Award for Creative Invention sponsored by the ACS Corporation Associates). Design of kinase inhibitor medicines utilizing protein-ligand structures and property-based efficiency