2. Academic Validation
  3. Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors

Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors

  • ACS Med Chem Lett. 2019 Oct 22;10(11):1549-1553. doi: 10.1021/acsmedchemlett.9b00381.
Dries J H De Clercq 1 2,  David E Heppner 1 2,  Ciric To 3 4 5,  Jaebong Jang 1 2,  Eunyoung Park 1 2,  Cai-Hong Yun 1 2 6,  Mierzhati Mushajiang 3,  Bo Hee Shin 3,  Thomas W Gero 1 2,  David A Scott 1 2,  Pasi A Jänne 3 4 5 7,  Michael J Eck 1 2,  Nathanael S Gray 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 3 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 5 Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 6 Department of Biochemistry and Biophysics, Peking University Health Science Center, Beijing 100191, China.
  • 7 Belfer Center for Applied Cancer Science, Boston, Massachusetts 02215, United States.
PMID: 31749909 DOI: 10.1021/acsmedchemlett.9b00381
Abstract

Allosteric kinase inhibitors represent a promising new therapeutic strategy for targeting kinases harboring oncogenic driver mutations in cancers. Here, we report the discovery, optimization, and structural characterization of allosteric mutant-selective EGFR inhibitors comprising a 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one scaffold. Our structure-based medicinal chemistry effort yielded an inhibitor (3) of the EGFR(L858R/T790M) and EGFR(L858R/T790M/C797S) mutants with an IC50 of ∼10 nM and high selectivity, as assessed by kinome profiling. Further efforts to develop allosteric dibenzodiazepinone inhibitors may serve as the basis for new therapeutic options for targeting drug-resistant EGFR mutations.

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