HJM-561, a Potent, Selective, and Orally Bioavailable EGFR PROTAC that Overcomes Osimertinib-Resistant EGFR Triple Mutations.

Abstract

The 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 patients with NSCLC 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 antitumor 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.