PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models.
PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models.
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DOI：
10.1016/j.ccell.2015.05.010
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发表时间：
2015-07-13
期刊：
影响因子：
50.3
通讯作者：
Smeal T
中科院分区：
文献类型：
--
作者：
Zou HY;Friboulet L;Kodack DP;Engstrom LD;Li Q;West M;Tang RW;Wang H;Tsaparikos K;Wang J;Timofeevski S;Katayama R;Dinh DM;Lam H;Lam JL;Yamazaki S;Hu W;Patel B;Bezwada D;Frias RL;Lifshits E;Mahmood S;Gainor JF;Affolter T;Lappin PB;Gukasyan H;Lee N;Deng S;Jain RK;Johnson TW;Shaw AT;Fantin VR;Smeal T
我们报告了PF-06463922的临床前评价，PF-06463922是一种强效的脑渗透性ALK/ROS 1抑制剂。与其他临床可用的ALK抑制剂相比，PF-06463922对所有已知的临床获得性ALK突变（包括高度耐药的G1202 R突变体）显示出上级效力。此外，PF-06463922给药导致EML 4-ALK驱动的脑转移消退，从而以上级方式延长小鼠生存期。最后，PF-06463922在各种临床前研究中表现出高选择性和安全范围。这些结果表明，PF-06463922将高度有效治疗ALK驱动的肺癌患者，包括因继发性ALK激酶结构域突变和/或因脑转移控制失败而使用临床可用ALK抑制剂复发的患者。
We report the preclinical evaluation of PF-06463922, a potent and brain penetrant ALK/ROS1 inhibitor. Compared to 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 due to secondary ALK kinase domain mutations and/or due to the failed control of brain metastases.