2. Academic Validation
  3. Discovery of a potent dual ALK and EGFR T790M inhibitor

Discovery of a potent dual ALK and EGFR T790M inhibitor

  • Eur J Med Chem. 2017 Aug 18:136:497-510. doi: 10.1016/j.ejmech.2017.04.079.
Jaebong Jang 1,  Jung Beom Son 2,  Ciric To 3,  Magda Bahcall 4,  So Young Kim 2,  Seock Yong Kang 2,  Mierzhati Mushajiang 4,  Younho Lee 2,  Pasi A Jänne 5,  Hwan Geun Choi 6,  Nathanael S Gray 7
Affiliations

Affiliations

  • 1 Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, United States.
  • 2 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.
  • 3 Harvard Medical School, Boston, MA 02115, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States.
  • 4 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States.
  • 5 Harvard Medical School, Boston, MA 02115, United States; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, United States; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, United States.
  • 6 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea. Electronic address: hgchoi@dgmif.re.kr.
  • 7 Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, United States. Electronic address: nathanael_gray@dfci.harvard.edu.
PMID: 28528303 DOI: 10.1016/j.ejmech.2017.04.079
Abstract

The mutational activations of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) are validated oncogenic events and the targets of approved drugs to treat non-small cell lung Cancer (NSCLC). Here we report highly potent dual small molecule inhibitors of both ALK and EGFR, particularly the T790M mutant which confers resistance to first generation EGFR inhibitors. Dual ALK/EGFR inhibitors may provide an efficient approach to prevent resistance that arises as a consequence of clinically reported reciprocal activation mechanisms. Our lead compound 7c displayed remarkable inhibitory activities against both ALK and EGFR in enzymatic and cellular assays. We demonstrate that 7c is capable of recapitulating the signaling effects and antiproliferative activity of combined treatment with the approved ALK inhibitor ceritinib and T790M EGFR inhibitor osimertinib against patient-derived non-small cell lung Cancer cell line, DFCI032 which harbors both EML4-ALK and activated EGFR.

Keywords

ALK; Dual inhibitor; EGFR T790M; Non-small cell lung cancer; Rational drug design.

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