LAUSR

Abnormal expression and activation of Epidermal Growth Factor Receptor (EGFR) contribute to malignancy development, especially in non-small cell lung cancers (NSCLCs). Although the first- to third-generation EGFR small molecule inhibitors have made significant progress in the treatment of EGFR mutant NSCLC patients, acquired mutations have been developed rapidly, resulting in drug resistance. Targeted protein degradation (TPD) technologies including PROteolysis Targeting Chimeras (PROTACs) have recently emerged as a promising alternative modality to address the confronting issues of small molecule inhibitors such as drug resistance. Recently, we have developed a series of heterobifunctional degraders of EGFR mutant proteins, which showed strong degradation ability against a variety of mutant EGFRs including triple mutants with C797S. DC50 (half-maximal degradation concentrations) values of the degraders were obtained using HiBiT assay in NCI-H1975 (EGFR L858R/T790M), HCC827 (EGFR Del19), and H1299 (EGFR WT) cells. Our lead compounds demonstrated excellent EGFR degradation potency with high selectivity against EGFR wild type. Moreover, C-09045, C-09066, and C-13951 strongly inhibited the cell growth of Ba/F3 cells harboring one of the EGFR mutations including L858R/C797S, Del19/C797S, L858R/T790M/C797S, Del19/T790M/C797S, and Exon20 NPH insertion. By contrast, these compounds showed much weaker potency in normal lung fibroblast (HFL-1) and Ba/F3 cells harboring EGFR wild-type. In PK analysis, C-09066 showed good oral bioavailability in mice (F%=41.4) with desirable pharmacokinetic parameters and robust tumor growth inhibition efficacy in the NCI-H1975 EGFR L858R/T790M/C797S xenograft and the Ba/F3 Del19/C797S allograft mouse models. In summary, we have identified selective, potent, and orally bioavailable degraders of various EGFR mutant proteins with broad spectrum anti-tumor efficacy both in vitro and in vivo. Citation Format: Dong Hyuk Ki, Min Sung Joo, Joonwoo Nam, Hunmi Choi, Kyoungwan Seo, Eun-Jung Kim, Jiyeon Kim, Chulwon Kim, Jimmy Taiguang Jin, Wooseok Han. Discovery of novel heterobifunctional degraders of mutant EGFR proteins for NSCLCs harboring various EGFR mutations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5006.