PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations

Zou Helen Y.; Li Qiuhua; Engstrom Lars D.West MelissaAppleman VickyWong Katy A.McTigue MicheleDeng Ya-LiLiu WeiBrooun AlexeiTimofeevski SergeiMcDonnell Scott R. P.Jiang PingFalk Matthew D.Lappin Patrick B.Affolter TimothyNichols TimHu WenyueLam JustineJohnson Ted W.Smeal TodCharest AlFantin Valeria R.

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations

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PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations

机译：PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations

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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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《Proceedings of the National Academy of Sciences of the United States of America》 |2015年第11期|3493-3498|共6页
作者
Zou Helen Y.; Li Qiuhua; Engstrom Lars D.West MelissaAppleman VickyWong Katy A.McTigue MicheleDeng Ya-LiLiu WeiBrooun AlexeiTimofeevski SergeiMcDonnell Scott R. P.Jiang PingFalk Matthew D.Lappin Patrick B.Affolter TimothyNichols TimHu WenyueLam JustineJohnson Ted W.Smeal TodCharest AlFantin Valeria R.;
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作者单位

Pfizer Worldwide Res, Oncol Res Unit, La Jolla, CA 92121 USA;

Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA 02111 USA;

Pfizer Worldwide Res, Oncol Med Chem, La Jolla, CA 92121 USAPfizer Worldwide Res, Drug Safety Res & Dev, La Jolla, CA 92121 USAPfizer Worldwide Res, Pharmacokinet Dynam Metab, La Jolla, CA 92121 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
PF-06463922; ROS1; kinase inhibitor;

PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations

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