Discovery of mobocertinib, a potent, oral inhibitor of EGFR exon 20 insertion mutations in non-small cell lung cancer.

In the treatment of non-small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure-activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy.

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Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wei-Sheng Huang, Feng Li, Yongjin Gong, Yun Zhang, Willmen Youngsaye, Yongjin Xu, Xiaotian Zhu, Matthew T. Greenfield, Anna Kohlmann, Paul M. Taslimi, Angela Toms, Stephan G. Zech, Tianjun Zhou, Biplab Das, Hyun G. Jang, Meera Tugnait, Yihua E. Ye, Francois Gonzalvez, Theresa E. Baker, Sara Nadworny, Yaoyu Ning, Scott D. Wardwell, Sen Zhang, Tim Clackson, Narayana I. Narasimhan, Victor M. Rivera, David C. Dalgarno, William C. Shakespeare are former employees of ARIAD. Huang, Yun Zhang, Ye, Nadworny, Sen Zhang, Clackson, Narasimhan, Rivera, Dalgarno, and Shakespeare are employees and shareholders of Theseus Pharmaceuticals. Alexandra E. Gould, and Weston Lane are former employees of Takeda. Yongbo Hu is an employee of Takeda. Robert J. Skene and Hua Zou are employees and shareholders of Takeda. Gong is an employee and shareholder of UCB. Youngsaye is an employee and shareholder of Exo Therapeutics. Xu is an employee and shareholder of FogPharma. Zhu is an employee and shareholder of Regor Pharmaceuticals, Inc. Greenfield is an employee and shareholder of Verve Therapeutics. Kohlmann is an employee and shareholder of Black Diamond Therapeutics. Taslimi is an employee and shareholder of Merck. Toms is an employee and shareholder of Nimbus Therapeutics. Zech is an employee and shareholder of Amgen Inc. Das is an employee and shareholder of Pyxis Oncology. Jang is an employee and shareholder of Wave Life Sciences. Tugnait is an employee and shareholder of Cerevel Therapeutics. Gonzalvez is an employee and shareholder of Aligos Therapeutics. Baker is an employee and shareholder of MOMA Therapeutics. Wardwell is an employee and shareholder of Blueprint Medicines. Gould is an employee of Broad Institute of MIT and Harvard. Lane is an employee and shareholder of Treeline Biosciences.