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

Rebecca Newton; Bohdan Waszkowycz; Chitra Seewooruthun; Daniel Burschowsky; Mark Richards; Samantha Hitchin; Habiba Begum; Amanda Watson; Eleanor French; Niall Hamilton; Stuart Jones; Li-Ying Lin; Ian Waddell; Aude Echalier; Richard Bayliss; Allan M Jordan; Donald Ogilvie

doi:10.1021/acsmedchemlett.9b00615

Discovery and Optimization of wt-RET/KDR-Selective Inhibitors of RET^V804M Kinase

ACS Med Chem Lett. 2020 Feb 28;11(4):497-505. doi: 10.1021/acsmedchemlett.9b00615. eCollection 2020 Apr 9.

Authors

Rebecca Newton¹, Bohdan Waszkowycz¹, Chitra Seewooruthun², Daniel Burschowsky², Mark Richards³, Samantha Hitchin¹, Habiba Begum¹, Amanda Watson¹, Eleanor French¹, Niall Hamilton¹, Stuart Jones¹, Li-Ying Lin⁴, Ian Waddell¹, Aude Echalier², Richard Bayliss³, Allan M Jordan¹, Donald Ogilvie¹

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.

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 RET^V804M 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.

Abstract

Grants and funding