title: Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation.
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.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Longwood Center LC-2209, Boston, MA 02115, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hatcher
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue Boston, MA 02215, USA.
authors.forename: Magda
authors.initials: M
authors.lastname: Bahcall
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.affiliation: Department of Pediatric Haematology and Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA 02215.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.affiliation: Department of Pediatric Haematology and Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA 02215.
authors.forename: Rani
authors.initials: R
authors.lastname: George
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue Boston, MA 02215, USA.|Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Longwood Center LC-2209, Boston, MA 02115, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002227:Carbazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D051379:Mice; D062105:Molecular Docking Simulation; D041681:NIH 3T3 Cells; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: D002227:Carbazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib