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PDBsum entry 5cao
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Transferase/transferase inhibitor
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PDB id
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5cao
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References listed in PDB file
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Key reference
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Title
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Noncovalent mutant selective epidermal growth factor receptor inhibitors: a lead optimization case study.
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Authors
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R.Heald,
K.K.Bowman,
M.C.Bryan,
D.Burdick,
B.Chan,
E.Chan,
Y.Chen,
S.Clausen,
B.Dominguez-Fernandez,
C.Eigenbrot,
R.Elliott,
E.J.Hanan,
P.Jackson,
J.Knight,
H.La,
M.Lainchbury,
S.Malek,
S.Mann,
M.Merchant,
K.Mortara,
H.Purkey,
G.Schaefer,
S.Schmidt,
E.Seward,
S.Sideris,
L.Shao,
S.Wang,
K.Yeap,
I.Yen,
C.Yu,
T.P.Heffron.
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Ref.
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J Med Chem, 2015,
58,
8877-8895.
[DOI no: ]
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PubMed id
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Abstract
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Because of their increased activity against activating mutants, first-generation
epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable
success in treating non-small-cell lung cancer (NSCLC) patients, but acquired
resistance, through a secondary mutation of the gatekeeper residue, means that
clinical responses only last for 8-14 months. Addressing this unmet medical need
requires agents that can target both of the most common double mutants:
T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a
noncovalent double mutant selective lead compound was optimized using a strategy
focused on the structure-guided increase in potency without added lipophilicity
or reduction of three-dimensional character. Following successive rounds of
design and synthesis it was discovered that cis-fluoro substitution on
4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial,
and specific potency gain through direct interaction with the enzyme and/or
effects on the proximal ligand oxygen atom. Further development of the
fluorohydroxypiperidine series resulted in the identification of a pair of
diastereomers that showed 50-fold enzyme and cell based selectivity for T790M
mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in
vivo xenograft model.
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