2. Academic Validation
  3. Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation

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.
John M Hatcher  # 1 2,  Magda Bahcall  # 3,  Hwan Geun Choi 1,  Yang Gao 4,  Taebo Sim 5,  Rani George 4,  Pasi A Jänne 3 6,  Nathanael S Gray 1 2
Affiliations

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.
PMID: 26568289 DOI: 10.1021/acs.jmedchem.5b01136
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.

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