TY - JOUR
T1 - Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation
AU - Hatcher, John M.
AU - Bahcall, Magda
AU - Choi, Hwan Geun
AU - Gao, Yang
AU - Sim, Taebo
AU - George, Rani
AU - Jänne, Pasi A.
AU - Gray, Nathanael S.
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/12/10
Y1 - 2015/12/10
N2 - 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, JH-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing.
AB - 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, JH-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing.
UR - http://www.scopus.com/inward/record.url?scp=84949921074&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.5b01136
DO - 10.1021/acs.jmedchem.5b01136
M3 - Article
C2 - 26568289
AN - SCOPUS:84949921074
SN - 0022-2623
VL - 58
SP - 9296
EP - 9308
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 23
ER -
