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

• Published in: ACS medicinal chemistry letters Vol. 10; no. 11; pp. 1549 - 1553
• Main Authors: De Clercq, Dries J. H, Heppner, David E, To, Ciric, Jang, Jaebong, Park, Eunyoung, Yun, Cai-Hong, Mushajiang, Mierzhati, Shin, Bo Hee, Gero, Thomas W, Scott, David A, Jänne, Pasi A, Eck, Michael J, Gray, Nathanael S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.11.2019; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; non-small cell lung cancer; kinase inhibitor; dibenzodiazepinone; allosteric inhibitor; mutant-selective; EGFR; CELL LUNG-CANCER; POTENT; RESISTANCE; ACTIVATING MUTATIONS; AZD9291
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.9b00381

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.