Rationally designed allosteric EGFR degrader SC3499 (IN-207375) selectively eliminates mutant EGFR and overcomes osimertinib resistance in non-small cell lung cancer

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated remarkable therapeutic efficacy in patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. However, acquired resistance often driven by secondary EGFR mutations remains a major clinical challenge. Although the third-generation covalent inhibitor osimertinib effectively overcomes T790M-mediated resistance and is widely used as first-line therapy. Nevertheless, resistance to osimertinib eventually develops, and patients with the EGFR L858R mutation often experience less durable responses than those with exon 19 deletions. Therapeutic options for patients who progress after osimertinib remain limited. Targeted protein degraders act through a catalytic, event-driven mechanism that can reduce on-target resistance relative to occupancy-driven inhibitors. SC3499 is an orally active, allosteric bifunctional degrader rationally designed to selectively target mutant EGFR containing the oncogenic L858R mutation. In preclinical studies, SC3499 demonstrated potent and durable antitumor activity in both in vitro and in vivo L858R-driven NSCLC models. Importantly, SC3499 maintained full activity against multiple resistance mutations, including L858R/C797S, L858R/T790M, and L858R/T790M/C797S, which confer resistance to approved EGFR TKIs such as osimertinib. In in vivo studies, SC3499 exhibited favorable pharmacokinetic properties, excellent oral bioavailability, and induced marked tumor regression with once-daily oral dosing. Broad kinase profiling showed exceptional kinase selectivity, and global proteomic analysis confirmed selective degradation of mutant EGFR without affecting unrelated proteins or other cereblon (CRBN) substrates. These results support SC3499 as a promising, orally active, allosteric EGFR degrader capable of overcoming resistance to current EGFR-targeted therapies, including osimertinib, and providing durable antitumor responses in EGFR-mutant NSCLC.