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PDBsum entry 6g9h
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Signaling protein
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PDB id
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6g9h
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References listed in PDB file
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Key reference
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Title
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Fragment-Based discovery of a potent, Orally bioavailable inhibitor that modulates the phosphorylation and catalytic activity of erk1/2.
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Authors
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T.D.Heightman,
V.Berdini,
H.Braithwaite,
I.M.Buck,
M.Cassidy,
J.Castro,
A.Courtin,
J.E.H.Day,
C.East,
L.Fazal,
B.Graham,
C.M.Griffiths-Jones,
J.F.Lyons,
V.Martins,
S.Muench,
J.M.Munck,
D.Norton,
M.O'Reilly,
N.Palmer,
P.Pathuri,
M.Reader,
D.C.Rees,
S.J.Rich,
C.Richardson,
H.Saini,
N.T.Thompson,
N.G.Wallis,
H.Walton,
N.E.Wilsher,
A.J.Woolford,
M.Cooke,
D.Cousin,
S.Onions,
J.Shannon,
J.Watts,
C.W.Murray.
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Ref.
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J Med Chem, 2018,
61,
4978-4992.
[DOI no: ]
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PubMed id
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Abstract
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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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