Drugging the undruggable: a computational chemist's view of KRASG12C. Issue 4 (29th March 2021)

• Record Type: Journal Article
• Authors: Bodnarchuk, Michael S.; Cassar, Doyle J.; Kettle, Jason G.; Robb, Graeme; Ward, Richard A.
• Is Part Of: RSC medicinal chemistry. Volume 12:Issue 4(2021)
• Page Start: 609
• Page End: 614
• Publication Date: 2021-03-29
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1039/d1md00055a
• Languages: English
• ISSNs: 2632-8682

Abstract

Abstract : Starting from a literature KRAS G12C inhibitor, in this article we show how computational chemistry can help guide the process to a highly optimised tetracyclic series which demonstrates strong tumour regression. Abstract : In recent years, the emergence of targeted covalent inhibitors which bind to the G12C mutant of KRAS have offered a solution to this previously intractable target. Inhibitors of KRAS G12C tend to be structurally complex, displaying features such as atropisomerism, chiral centres and a reactive covalent warhead. Such molecules result in lengthy and challenging syntheses, and as a consequence critical decisions need to be made at the design level to maximise the chances of success. Here we take a retrospective look into how computational chemistry can help guide and prioritise medicinal chemistry efforts in the context of a series of conformationally restricted tetracyclic quinolines.