Distinct Amino Acid-Based PROTACs Target Oncogenic Kinases for Degradation in Non-Small Cell Lung Cancer (NSCLC)

Proteolysis-targeting chimeras (PROTACs) selectively
eliminate
detrimental proteins by exploiting the ubiquitin-proteasome system
(UPS), representing a promising therapeutic strategy against various
diseases. Effective adaptations of degradation signal sequences and
E3 ligases for PROTACs remain limited. Here, we employed three amino
acidsGly, Pro, and Lysas the ligand to recruit the
corresponding E3 ligases: CRL2ZYG11B/ZER1, GID4, and UBRs,
to degrade EML4-ALK and mutant EGFR, two oncogenic drivers in NSCLC.
We found that the extent of EML4-ALK and EGFR reduction can be easily
fine-tuned by using different degradation signals. These amino acid-based
PROTACs, termed AATacs, hindered proliferation and induced cell cycle
arrest and apoptosis of NSCLC cells in vitro. Compared to other PROTACs,
AATacs are small, interchangeable but with different degradation efficiency.
Our study further expands the repertoire of E3 ligases and their ligands
for PROTAC application, improving the versatility and utility of targeted
protein degradation for therapeutic purposes.