Distinct Amino\nAcid-Based PROTACs Target Oncogenic\nKinases for Degradation in Non-Small Cell Lung Cancer (NSCLC)

Proteolysis-targeting chimeras (PROTACs) selectively\neliminate\ndetrimental proteins by exploiting the ubiquitin-proteasome system\n(UPS), representing a promising therapeutic strategy against various\ndiseases. Effective adaptations of degradation signal sequences and\nE3 ligases for PROTACs remain limited. Here, we employed three amino\nacidsGly, Pro, and Lysas the ligand to recruit the\ncorresponding E3 ligases: CRL2<sup>ZYG11B/ZER1</sup>, GID4, and UBRs,\nto degrade EML4-ALK and mutant EGFR, two oncogenic drivers in NSCLC.\nWe found that the extent of EML4-ALK and EGFR reduction can be easily\nfine-tuned by using different degradation signals. These amino acid-based\nPROTACs, termed AATacs, hindered proliferation and induced cell cycle\narrest and apoptosis of NSCLC cells in vitro. Compared to other PROTACs,\nAATacs are small, interchangeable but with different degradation efficiency.\nOur study further expands the repertoire of E3 ligases and their ligands\nfor PROTAC application, improving the versatility and utility of targeted\nprotein degradation for therapeutic purposes.