Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation

被引：38

作者：

Hatcher, John M. ^{[1
,4
]}

Bahcall, Magda ^{[2
]}

Choi, Hwan Geun ^{[1
]}

Gao, Yang ^{[5
,6
]}

Sim, Taebo ^{[7
,8
]}

George, Rani ^{[5
,6
]}

Jaenne, Pasi A. ^{[2
,3
]}

Gray, Nathanael S. ^{[1
,4
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[5] Dana Farber Canc Inst, Dept Pediat Haematol & Oncol, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02215 USA

[7] Korea Inst Sci & Technol, Chem Kinom Res Ctr, Seoul 136791, South Korea

[8] Korea Univ, KU KIST Grad Sch Converging Sci & Technol, Seoul 136713, South Korea

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 23期

基金：

新加坡国家研究基金会; 美国国家卫生研究院;

关键词：

CELL LUNG-CANCER; ACTIVATING MUTATIONS; ALK REARRANGEMENTS; TYROSINE KINASE; CRIZOTINIB; NEUROBLASTOMA; IDENTIFICATION; CHEMOTHERAPY; EXPRESSION; RECEPTOR;

D O I：

10.1021/acs.jmedchem.5b01136

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The treatment of patients with advanced non-small-cell lung cancer harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small-molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms, leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of "second-generation" ALK inhibitors, including alectinib and ceritinib, that overcome some of the mutations leading to resistance. However, most of the reported ALK inhibitors do not show inhibition of the G1202R mutant, which is one of the most common mutations. Herein, we report the development of a structural analogue of alectinib (JH-VIII-157-02) that is potent against the G1202R mutant as well as a variety of other frequently observed mutants. In addition, JET-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing.

引用

页码：9296 / 9308

页数：13

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