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

Dries J H De Clercq; David E Heppner; Ciric To; Jaebong Jang; Eunyoung Park; Cai-Hong Yun; Mierzhati Mushajiang; Bo Hee Shin; Thomas W Gero; David A Scott; Pasi A Jänne; Michael J Eck; Nathanael S Gray

doi:10.1021/acsmedchemlett.9b00381

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. eCollection 2019 Nov 14.

Authors

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 Mushajiang³, Bo Hee Shin³, 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

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.

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.

Abstract

Grants and funding