The GTP-hydrolyzing enzyme K-Ras is a key molecular switch that controls numerous cell-signaling pathways. Its over activation due to mutation is associated with ~25% all human tumors and up to 90% of specific tumor types such as pancreatic cancer. Thus, a drug that directly and selectively inhibits K-Ras would be a game changer in cancer therapy. However, finding such a drug has remained elusive. One of the challenges was that the catalytic site is an unsuitable target because it is conserved in many families of GTPases that are unrelated to K-Ras signaling, which would lead to problems of selectivity and toxicity. Even if selective inhibitors of the active site were identified, the high concentration and affinity of cellular GTP and GDP would make competitive inhibition impractical. Since K-Ras is a small, monomeric protein with a somewhat flat surface, alternative ligand binding sites were not seriously considered. As a result, it was thought that direct inhibition of K-Ras would be impossible and efforts were diverted to indirect inhibition, such as interfering with its plasma membrane binding which to date remains unsuccessful. Recent advances have allowed for a re-imagination of direct inhibition, and it is now well accepted that K-Ras is an allosteric enzyme with up to four allosteric ligand-binding sites. Building on these developments, we performed a large-scale high-throughput <i>in silico</i> screening against many different ensembles of solution K-Ras structures and assessed the Ras binding potential and inhibitory activity of the predicted hits by NMR, fluorescence-based binding assays, and assays in cells expressing oncogenic mutant K-Ras. I will discuss the discovery and initial characterization of a number of novel compounds and their potential as starting points for the development of anti-Ras lead compounds.<br/>

Structure-based design of allosteric K-Ras inhibitors

253rd National Meeting (2017)

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