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PDBsum entry 4uxl
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References listed in PDB file
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Key reference
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Title
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Pf-06463922 is a potent and selective next-Generation ros1/alk inhibitor capable of blocking crizotinib-Resistant ros1 mutations.
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Authors
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H.Y.Zou,
Q.Li,
L.D.Engstrom,
M.West,
V.Appleman,
K.A.Wong,
M.Mctigue,
Y.L.Deng,
W.Liu,
A.Brooun,
S.Timofeevski,
S.R.Mcdonnell,
P.Jiang,
M.D.Falk,
P.B.Lappin,
T.Affolter,
T.Nichols,
W.Hu,
J.Lam,
T.W.Johnson,
T.Smeal,
A.Charest,
V.R.Fantin.
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Ref.
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Proc Natl Acad Sci U S A, 2015,
112,
3493-3498.
[DOI no: ]
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PubMed id
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Abstract
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Oncogenic c-ros oncogene1 (ROS1) fusion kinases have been identified in a
variety of human cancers and are attractive targets for cancer therapy. The
MET/ALK/ROS1 inhibitor crizotinib (Xalkori, PF-02341066) has demonstrated
promising clinical activity in ROS1 fusion-positive non-small cell lung cancer.
However, emerging clinical evidence has shown that patients can develop
resistance by acquiring secondary point mutations in ROS1 kinase. In this study
we characterized the ROS1 activity of PF-06463922, a novel, orally available,
CNS-penetrant, ATP-competitive small-molecule inhibitor of ALK/ROS1. In vitro,
PF-06463922 exhibited subnanomolar cellular potency against oncogenic ROS1
fusions and inhibited the crizotinib-refractory ROS1(G2032R) mutation and the
ROS1(G2026M) gatekeeper mutation. Compared with crizotinib and the
second-generation ALK/ROS1 inhibitors ceritinib and alectinib, PF-06463922
showed significantly improved inhibitory activity against ROS1 kinase. A crystal
structure of the PF-06463922-ROS1 kinase complex revealed favorable interactions
contributing to the high-affinity binding. In vivo, PF-06463922 showed marked
antitumor activity in tumor models expressing FIG-ROS1, CD74-ROS1, and the
CD74-ROS1(G2032R) mutation. Furthermore, PF-06463922 demonstrated antitumor
activity in a genetically engineered mouse model of FIG-ROS1 glioblastoma. Taken
together, our results indicate that PF-06463922 has potential for treating ROS1
fusion-positive cancers, including those requiring agents with CNS-penetrating
properties, as well as for overcoming crizotinib resistance driven by ROS1
mutation.
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