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PDBsum entry 6ut0
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Hydrolase/inhibitor
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PDB id
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6ut0
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References listed in PDB file
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Key reference
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Title
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Identification of the clinical development candidate mrtx849, A covalent krasg12c inhibitor for the treatment of cancer.
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Authors
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J.B.Fell,
J.P.Fischer,
B.R.Baer,
J.F.Blake,
K.Bouhana,
D.M.Briere,
K.D.Brown,
L.E.Burgess,
A.C.Burns,
M.R.Burkard,
H.Chiang,
M.J.Chicarelli,
A.W.Cook,
J.J.Gaudino,
J.Hallin,
L.Hanson,
D.P.Hartley,
E.J.Hicken,
G.P.Hingorani,
R.J.Hinklin,
M.J.Mejia,
P.Olson,
J.N.Otten,
S.P.Rhodes,
M.E.Rodriguez,
P.Savechenkov,
D.J.Smith,
N.Sudhakar,
F.X.Sullivan,
T.P.Tang,
G.P.Vigers,
L.Wollenberg,
J.G.Christensen,
M.A.Marx.
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Ref.
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J Med Chem, 2020,
63,
6679-6693.
[DOI no: ]
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PubMed id
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Abstract
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Capping off an era marred by drug development failures and punctuated by waning
interest and presumed intractability toward direct targeting of KRAS, new
technologies and strategies are aiding in the target's resurgence. As previously
reported, the tetrahydropyridopyrimidines were identified as irreversible
covalent inhibitors of KRASG12C that bind in the switch-II pocket of
KRAS and make a covalent bond to cysteine 12. Using structure-based drug design
in conjunction with a focused in vitro absorption, distribution, metabolism and
excretion screening approach, analogues were synthesized to increase the potency
and reduce metabolic liabilities of this series. The discovery of the clinical
development candidate MRTX849 as a potent, selective covalent inhibitor
of KRASG12C is described.
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