HJM-561, a potent, selective and orally bioavailable EGFR PROTAC that overcomes osimertinib-resistant EGFR triple mutations

• Published in: Molecular cancer therapeutics Vol. 21; no. 7; pp. 1060 - 1066
• Main Authors: Du, Yong, Chen, Yongfeng, Wang, Yuxia, Chen, Jinju, Lu, Xiaorong, Zhang, Li, Li, Yan, Wang, Zhaofu, Ye, Guozhong, Zhang, George
• Format: Journal Article
• Language: English
• Published: United States 05.07.2022
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-21-0835

The epidermal growth factor receptor (EGFR) C797S mutation is the most common on-target resistance mechanism to osimertinib in patients with advanced non-small-cell lung cancer (NSCLC). Currently there are no effective treatment options for NSCLC patients harboring EGFR C797S triple mutants (Del19/T790M/C797S and L858R/T790M/C797S). Herein, we report an orally bioavailable EGFR PROTAC, HJM-561, which selectively degrades the EGFR C797S-containing triple mutants. HJM-561 potently inhibits the proliferation of Del19/T790M/C797S and L858R/T790M/C797S Ba/F3 cells while sparing cells expressing wild type EGFR. Oral administration of HJM-561 shows robust anti-tumor activity in EGFR Del19/T790M/C797S-driven Ba/F3 CDX and PDX models that were resistant to osimertinib treatment. Taken together, our results suggest that HJM-561 is a promising therapeutic option for overcoming EGFR triple mutation-mediated drug resistance in NSCLC.