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PDBsum entry 5ug9
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Transferase/transferase inhibitor
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PDB id
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5ug9
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References listed in PDB file
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Key reference
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Title
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Discovery of n-((3r,4r)-4-Fluoro-1-(6-((3-Methoxy-1-Methyl-1h-Pyrazol-4-Yl)amino)-9-Methyl-9h-Purin-2-Yl)pyrrolidine-3-Yl)acrylamide (pf-06747775) through structure-Based drug design: a high affinity irreversible inhibitor targeting oncogenic egfr mutants with selectivity over wild-Type egfr.
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Authors
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S.Planken,
D.C.Behenna,
S.K.Nair,
T.O.Johnson,
A.Nagata,
C.Almaden,
S.Bailey,
T.E.Ballard,
L.Bernier,
H.Cheng,
S.Cho-Schultz,
D.Dalvie,
J.G.Deal,
D.M.Dinh,
M.P.Edwards,
R.A.Ferre,
K.S.Gajiwala,
M.Hemkens,
R.S.Kania,
J.C.Kath,
J.Matthews,
B.W.Murray,
S.Niessen,
S.T.Orr,
M.Pairish,
N.W.Sach,
H.Shen,
M.Shi,
J.Solowiej,
K.Tran,
E.Tseng,
P.Vicini,
Y.Wang,
S.L.Weinrich,
R.Zhou,
M.Zientek,
L.Liu,
Y.Luo,
S.Xin,
C.Zhang,
J.Lafontaine.
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Ref.
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J Med Chem, 2017,
60,
3002-3019.
[DOI no: ]
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PubMed id
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Abstract
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Mutant epidermal growth factor receptor (EGFR) is a major driver of
non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such
as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC
patients before resistance mechanisms render these inhibitors ineffective.
Secondary oncogenic EGFR mutations account for approximately 50% of relapses,
the most common being the gatekeeper T790M substitution that renders existing
therapies ineffective. The discovery of PF-06459988 (1), an irreversible
pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1
Herein, we describe our continued efforts to achieve potency across EGFR
oncogenic mutations and improved kinome selectivity, resulting in the discovery
of clinical candidate PF-06747775 (21), which provides potent EGFR activity
against the four common mutants (exon 19 deletion (Del), L858R, and double
mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and
desirable ADME properties. Compound 21 is currently being evaluated in phase-I
clinical trials of mutant EGFR driven NSCLC.
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