Structure-Guided Optimization of p62-Directed AUTOTACs for Efficient EGFR/VEGFR2 Degradation and Antitumor Efficacy.

Receptor tyrosine kinases (RTKs) are core cancer therapeutic targets, yet their integral membrane localization hinders efficient degradation by traditional ubiquitin-proteasome system (UPS)-based targeted protein degradation (TPD) strategies. Herein, we describe the structure-guided development of p62/SQSTM1-directed autophagy-targeting chimera (AUTOTAC) degraders targeting RTKs. Medicinal chemistry optimization yielded two potent AUTOTACs, 6d and 11bg, which selectively degrade EGFR and VEGFR2, respectively. Mechanistic studies confirmed that these degraders act via p62 recruitment and autophagy-lysosome pathway activation in a UPS-independent manner. 6d and 11bg exhibited robust antiproliferative, proapoptotic, and antimigratory effects in vitro, and 6d further demonstrated significant in vivo antitumor efficacy with good tolerability in xenograft models. This study validates AUTOTAC technology for RTK degradation, offering a new approach to address TKI resistance and broaden the TPD landscape.