Discovery and optimisation of wt-RET/KDR-selective inhibitors of RET V804M kinase

DOI: 10.1021/acsmedchemlett.9b00615

Authors: Rebecca Newton (Cancer Research UK Manchester Institute - University of Manchester) , Bohdan Waszkowycz (Cancer Research UK Manchester Institute - University of Manchester) , Chitra Seewooruthun (University of Leicester) , Daniel Burschowsky (University of Leicester) , Mark Richards (University of Leeds) , Samantha Hitchin (Cancer Research UK Manchester Institute - University of Manchester) , Habiba Begum (Cancer Research UK Manchester Institute - University of Manchester) , Amanda Watson (Cancer Research UK Manchester Institute - University of Manchester) , Eleanor French (Cancer Research UK Manchester Institute - University of Manchester) , Niall Hamilton (Cancer Research UK Manchester Institute - University of Manchester) , Stuart Jones (Cancer Research UK Manchester Institute - University of Manchester) , Li-ying Lin (Leicester Drug Discovery & Diagnostics Centre) , Ian Waddell (Cancer Research UK Manchester Institute - University of Manchester) , Aude Echalier (University of Leicester) , Richard Bayliss (University of Leeds) , Allan M. Jordan (Cancer Research UK Manchester Institute - University of Manchester) , Donald Ogilvie (Cancer Research UK Manchester Institute - University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: February 2020
Diamond Proposal Number(s): 8997

Abstract: A combination of focussed library and virtual screening, hit expansion and rational design has resulted in the development of a series of inhibitors of RETV804M kinase, the anticipated drug-resistant mutant of RET kinase. These agents do not inhibit the wild-type isoforms of RET or KDR and therefore offer a potential adjunct to RET inhibitors currently undergoing clinical evaluation.

Journal Keywords: RET; KDR; kinase inhibitor; virtual screening

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography