 |
PDBsum entry 5hg9
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/transferase inhibitor
|
PDB id
|
|
|
|
5hg9
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Discovery of 1-{(3r,4r)-3-[({5-Chloro-2-[(1-Methyl-1h-Pyrazol-4-Yl)amino]-7h-Pyrrolo[2,3-D]pyrimidin-4-Yl}oxy)methyl]-4-Methoxypyrrolidin-1-Yl}prop-2-En-1-One (pf-06459988), A potent, Wt sparing, Irreversible inhibitor of t790m-Containing egfr mutants.
|
|
|
Authors
|
|
H.Cheng,
S.K.Nair,
B.W.Murray,
C.Almaden,
S.Bailey,
S.Baxi,
D.Behenna,
S.Cho-Schultz,
D.Dalvie,
D.M.Dinh,
M.P.Edwards,
J.L.Feng,
R.A.Ferre,
K.S.Gajiwala,
M.D.Hemkens,
A.Jackson-Fisher,
M.Jalaie,
T.O.Johnson,
R.S.Kania,
S.Kephart,
J.Lafontaine,
B.Lunney,
K.K.Liu,
Z.Liu,
J.Matthews,
A.Nagata,
S.Niessen,
M.A.Ornelas,
S.T.Orr,
M.Pairish,
S.Planken,
S.Ren,
D.Richter,
K.Ryan,
N.Sach,
H.Shen,
T.Smeal,
J.Solowiej,
S.Sutton,
K.Tran,
E.Tseng,
W.Vernier,
M.Walls,
S.Wang,
S.L.Weinrich,
S.Xin,
H.Xu,
M.J.Yin,
M.Zientek,
R.Zhou,
J.C.Kath.
|
|
|
Ref.
|
|
J Med Chem, 2016,
59,
2005-2024.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical
benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately,
these patients' disease progresses, often driven by a second-site mutation in
the EGFR kinase domain (T790M). Another liability of the first generation drugs
is severe adverse events driven by inhibition of WT EGFR. As such, our goal was
to develop a highly potent irreversible inhibitor with the largest selectivity
ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT
EGFR. A unique approach to develop covalent inhibitors, optimization of
reversible binding affinity, served as a cornerstone of this effort. PF-06459988
was discovered as a novel, third generation irreversible inhibitor, which
demonstrates (i) high potency and specificity to the T790M-containing double
mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic
warhead, (iii) greatly reduced proteome reactivity relative to earlier
irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.
|
|
|
|
|
|
|
