HJ-004：一种强效、选择性的泛EGFR突变靶向蛋白降解剂（TPD），可有效克服EGFR突变型NSCLC中的奥希替尼耐药

Background: Although three generations of EGFR tyrosine kinase inhibitors (TKIs) have achieved remarkable clinical success, resistance driven by secondary EGFR mutations remains a major therapeutic challenge in non-small cell lung cancer (NSCLC). To address this unmet need, we developed HJ-004, a potent, selective, and orally bioavailable pan-EGFR mutation degrader that targets classical, rare, and exon 20 insertion mutations. Methods and Results: HJ-004 induces potent and selective degradation of mutant EGFR proteins, but not wild-type EGFR, in Ba/F3 and human cell lines harboring diverse EGFR alterations, with DC₅₀ values below 5 nM, and exhibits strong antiproliferative activity. Mechanistic studies confirmed E3 ligase-mediated ubiquitination and proteasomal degradation. In vivo , HJ-004 produces dose-dependent tumor regression in both murine and human-derived cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models carrying various resistant EGFR genotypes. Pharmacokinetic evaluation demonstrated favorable PK properties, including 30-40% oral bioavailability across multiple species and sustained exposure supporting once-daily dosing. Importantly, HJ-004 exhibits an approximately 10-fold therapeutic window in both mice and monkeys, without any notable skin rashes or diarrhea, indicating excellent selectivity and safety margin. Conclusions: HJ-004 represents a first-in-class pan-EGFR mutation targeted protein degrader that effectively overcomes osimertinib resistance across classical, rare, and exon 20 insertion variants. Its potent degradation activity, broad antitumor efficacy, and favorable pharmacokinetic and safety profiles support advancement into clinical development as a next-generation therapy for EGFR-mutated NSCLC. HJ-004 was independently developed by Jing Medicine Technology (Shanghai) Ltd., and has received IND clearance from both the U.S. FDA and China NMPA.