Issue 4, 2021

Drugging the undruggable: a computational chemist's view of KRASG12C

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 KRASG12C 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.

Graphical abstract: Drugging the undruggable: a computational chemist's view of KRASG12C

Supplementary files

Article information

Article type
Research Article
Submitted
19 feb 2021
Accepted
18 mar 2021
First published
29 mar 2021

RSC Med. Chem., 2021,12, 609-614

Drugging the undruggable: a computational chemist's view of KRASG12C

M. S. Bodnarchuk, D. J. Cassar, J. G. Kettle, G. Robb and R. A. Ward, RSC Med. Chem., 2021, 12, 609 DOI: 10.1039/D1MD00055A

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements