Discovery and Optimization of wt-RET/KDR-Selective Inhibitors of RETV804M Kinase

  • ACS Med Chem Lett. 2020 Feb 28;11(4):497-505. doi: 10.1021/acsmedchemlett.9b00615.
Rebecca Newton  1 ,  Bohdan Waszkowycz  1 ,  Chitra Seewooruthun  2 ,  Daniel Burschowsky  2 ,  Mark Richards  3 ,  Samantha Hitchin  1 ,  Habiba Begum  1 ,  Amanda Watson  1 ,  Eleanor French  1 ,  Niall Hamilton  1 ,  Stuart Jones  1 ,  Li-Ying Lin  4 ,  Ian Waddell  1 ,  Aude Echalier  2 ,  Richard Bayliss  3 ,  Allan M Jordan  1 ,  Donald Ogilvie  1
Affiliations
  • 1. Drug Discovery Unit, Cancer Research UK, Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, U.K.
  • 2. Department of Molecular and Cell Biology, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 7RH, U.K.
  • 3. Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, U.K.
  • 4. Leicester Drug Discovery & Diagnostics Centre (LD3), R407a, Hodgkin Building, Lancaster Road, Leicester LE1 7HB, U.K.
PMID: 32292556 DOI: 10.1021/acsmedchemlett.9b00615
Abstract

A combination of focused 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 (wt) isoforms of RET or KDR and therefore offer a potential adjunct to RET inhibitors currently undergoing clinical evaluation.

Products