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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
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
Discipline Tags:
Technical Tags: