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

John M Hatcher; Magda Bahcall; Hwan Geun Choi; Yang Gao; Taebo Sim; Rani George; Pasi A Jänne; Nathanael S Gray

doi:10.1021/acs.jmedchem.5b01136

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

J Med Chem. 2015 Dec 10;58(23):9296-9308. doi: 10.1021/acs.jmedchem.5b01136. Epub 2015 Nov 25.

Authors

John M Hatcher^#^{1

2}, Magda Bahcall^#³, Hwan Geun Choi¹, Yang Gao⁴, Taebo Sim⁵, Rani George⁴, Pasi A Jänne^{3

6}, Nathanael S Gray^{1

2}

Affiliations

¹ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
² Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Longwood Center LC-2209, Boston, MA 02115, USA.
³ Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue Boston, MA 02215, USA.
⁴ Department of Pediatric Haematology and Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA 02215.
⁵ Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 136-791, Korea KU-KIST; Graduate School of Converging Science and Technology, 145, Anam-ro, Seongbuk-gu, Seoul, 136-713, Korea.
⁶ Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Carbazoles / chemistry*
Carbazoles / pharmacokinetics
Carbazoles / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / enzymology
Carcinoma, Non-Small-Cell Lung / genetics
Cell Line, Tumor
Drug Resistance, Neoplasm
Humans
Lung / drug effects
Lung / metabolism
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Lung Neoplasms / genetics
Mice
Molecular Docking Simulation
NIH 3T3 Cells
Neuroblastoma / drug therapy
Neuroblastoma / enzymology
Neuroblastoma / genetics
Piperidines / chemistry*
Piperidines / pharmacokinetics
Piperidines / pharmacology*
Point Mutation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / chemistry
Receptor Protein-Tyrosine Kinases / genetics

Substances

Carbazoles
Piperidines
Protein Kinase Inhibitors
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases
alectinib

Abstract

Publication types

MeSH terms

Substances

Grants and funding