Design and synthesis of novel peptide-based degraders against wild type and gatekeeper mutants FGFR1 for the treatment of NSCLC.

Abstract

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related morbidity worldwide, with fibroblast growth factor receptor 1 (FGFR1) playing a pivotal role in its pathogenesis and progression. Although FGFR1-targeted therapies, particularly tyrosine kinase inhibitors (TKIs), have shown clinical efficacy, their utility is limited by acquired resistance and off-target toxicities. Here, building on established SignalTAC principles for lysosome-directed membrane protein degradation, we investigated whether an FGFR1-binding peptide (Pep1) could be converted into an FGFR1 degrader by C-terminal conjugation of degradation signal motifs. Systematic screening identified Pep-SignalTAC 2-3, which induces rapid lysosomal degradation of wild-type FGFR1, suppresses downstream signaling, and triggers apoptosis in FGFR1-dependent cellular models. Importantly, it exhibits comparable efficacy in cells harboring the FGFR1 V561 F/M gatekeeper mutation. In vivo, a hydrogel-based sustained-release formulation of Pep-SignalTAC 2-3 achieved marked and comparable FGFR1 reduction (75% in wild-type vs. 73% in mutant) and tumor growth inhibition (59% in wild-type vs. 55% in mutant) in H1581 (wild-type FGFR1) and L6-FGFR1V561M (gatekeeper mutant) xenograft models, without overt systemic toxicity. Together, these findings demonstrate the feasibility of Pep-SignalTACs as a promising FGFR1-targeted therapeutic platform that enables effective degradation of both wild-type and mutant FGFR1 in NSCLC.