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Fragment-based discovery of a potent, orally bioavailable inhibitor which modulates the phosphorylation and catalytic activity of ERK1/2

DOI: 10.1021/acs.jmedchem.8b00421 DOI Help

Authors: Tom D. Heightman (Astex Pharmaceuticals) , Valerio Berdini (Astex Pharmaceuticals) , Hannah Braithwaite (Astex Pharmaceuticals) , Ildiko Maria Buck (Astex Pharmaceuticals) , Megan Cassidy (Astex Pharmaceuticals) , Juan Castro (Astex Pharmaceuticals) , Aurelie Courtin (Astex Pharmaceuticals) , James E. H. Day (Astex Pharmaceuticals) , Charlotte East (Astex Pharmaceuticals) , Lynsey Fazal (Astex Pharmaceuticals) , Brent Graham (Astex Pharmaceuticals) , Charlotte M. Griffiths-jones (Astex Pharmaceuticals) , John F. Lyons (Astex Pharmaceuticals) , Vanessa Martins (Astex Pharmaceuticals) , Sandra Muench (Astex Pharmaceuticals) , Joanne M. Munck (Astex Pharmaceuticals) , David Norton (Astex Pharmaceuticals) , Marc O'reilly (Astex Pharmaceuticals) , Nick Palmer (Astex Pharmaceuticals) , Puja Pathuri (Astex Pharmaceuticals) , Michael Reader (Astex Pharmaceuticals) , David C. Rees (Astex Pharmaceuticals) , Sharna J. Rich (Astex Pharmaceuticals) , Caroline Richardson (Astex Pharmaceuticals) , Harpreet Saini (Astex Pharmaceuticals) , Neil T. Thompson (Astex Pharmaceuticals) , Nicola G. Wallis (Astex Pharmaceuticals) , Hugh Walton (Astex Pharmaceuticals) , Nicola E. Wilsher (Astex Pharmaceuticals) , Alison J.-a. Woolford (Astex Pharmaceuticals) , Michael Cooke (Sygnature Discovery Ltd) , David Cousin (Sygnature Discovery Ltd) , Stuart Onions (Sygnature Discovery Ltd) , Jonathan Shannon (Sygnature Discovery Ltd) , John Watts (Sygnature Discovery Ltd) , Christopher W. Murray (Sygnature Discovery Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: May 2018

Abstract: Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signalling through ERK1/2. Here we describe the fragment based generation of ERK1/2 inhibitors which block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization towards clinical pERK1/2 modulating ERK1/2 inhibitors.

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


Instruments: I02-Macromolecular Crystallography

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