| Literature DB >> 26144315 |
Helen Y Zou1, Luc Friboulet2, David P Kodack3, Lars D Engstrom1, Qiuhua Li1, Melissa West1, Ruth W Tang1, Hui Wang1, Konstantinos Tsaparikos1, Jinwei Wang1, Sergei Timofeevski1, Ryohei Katayama4, Dac M Dinh1, Hieu Lam1, Justine L Lam1, Shinji Yamazaki1, Wenyue Hu1, Bhushankumar Patel3, Divya Bezwada3, Rosa L Frias2, Eugene Lifshits2, Sidra Mahmood2, Justin F Gainor2, Timothy Affolter1, Patrick B Lappin1, Hovhannes Gukasyan1, Nathan Lee1, Shibing Deng1, Rakesh K Jain3, Ted W Johnson1, Alice T Shaw2, Valeria R Fantin1, Tod Smeal5.
Abstract
We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases.Entities:
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Year: 2015 PMID： 26144315 PMCID： PMC4504786 DOI： 10.1016/j.ccell.2015.05.010
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743