Journal of Medicinal Chemistry p. 4978 - 4992 (2018)
Update date:2022-08-16
Topics:
Heightman, Tom D.
Berdini, Valerio
Braithwaite, Hannah
Buck, Ildiko M.
Cassidy, Megan
Castro, Juan
Courtin, Aurélie
Day, James E. H.
East, Charlotte
Fazal, Lynsey
Graham, Brent
Griffiths-Jones, Charlotte M.
Lyons, John F.
Martins, Vanessa
Muench, Sandra
Munck, Joanne M.
Norton, David
O'Reilly, Marc
Palmer, Nick
Pathuri, Puja
Reader, Michael
Rees, David C.
Rich, Sharna J.
Richardson, Caroline
Saini, Harpreet
Thompson, Neil T.
Wallis, Nicola G.
Walton, Hugh
Wilsher, Nicola E.
Woolford, Alison J.-A.
Cooke, Michael
Cousin, David
Onions, Stuart
Shannon, Jonathan
Watts, John
Murray, Christopher W.
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 signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that 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 toward clinical pERK1/2 modulating ERK1/2 inhibitors.
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(2018)