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PDBsum entry 5j7h
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Transferase/transferase inhibitor
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PDB id
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5j7h
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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 brigatinib (ap26113), A phosphine oxide-Containing, Potent, Orally active inhibitor of anaplastic lymphoma kinase.
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Authors
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W.S.Huang,
S.Liu,
D.Zou,
M.Thomas,
Y.Wang,
T.Zhou,
J.Romero,
A.Kohlmann,
F.Li,
J.Qi,
L.Cai,
T.A.Dwight,
Y.Xu,
R.Xu,
R.Dodd,
A.Toms,
L.Parillon,
X.Lu,
R.Anjum,
S.Zhang,
F.Wang,
J.Keats,
S.D.Wardwell,
Y.Ning,
Q.Xu,
L.E.Moran,
Q.K.Mohemmad,
H.G.Jang,
T.Clackson,
N.I.Narasimhan,
V.M.Rivera,
X.Zhu,
D.Dalgarno,
W.C.Shakespeare.
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Ref.
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J Med Chem, 2016,
59,
4948-4964.
[DOI no: ]
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PubMed id
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Abstract
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In the treatment of echinoderm microtubule-associated protein-like 4
(EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer
(NSCLC), secondary mutations within the ALK kinase domain have emerged as a
major resistance mechanism to both first- and second-generation ALK inhibitors.
This report describes the design and synthesis of a series of
2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating
in identification of the investigational clinical candidate brigatinib. A unique
structural feature of brigatinib is a phosphine oxide, an overlooked but novel
hydrogen-bond acceptor that drives potency and selectivity in addition to
favorable ADME properties. Brigatinib displayed low nanomolar IC50s against
native ALK and all tested clinically relevant ALK mutants in both enzyme-based
biochemical and cell-based viability assays and demonstrated efficacy in
multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell
lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically
advanced phosphine oxide-containing drug candidate to date and is currently
being evaluated in a global phase 2 registration trial.
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