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

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

  • J Med Chem. 2024 Aug 22;67(16):13666-13680. doi: 10.1021/acs.jmedchem.4c00208.
Jianchao Zhang 1,  Xiao Chen 1,  Congli Chen 2,  Fengming Li 3,  Xiaoxiao Song 1,  Chaowei Liu 1,  Kefan Liao 1,  Ming-Yuan Su 1 4 5,  Chris Soon Heng Tan 3,  Lijing Fang 2,  Hai Rao 1 4
Affiliations

Affiliations

  • 1 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
  • 2 Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, China.
  • 3 Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China.
  • 4 Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen 518055, China.
  • 5 Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen 518055, China.
PMID: 39114932 DOI: 10.1021/acs.jmedchem.4c00208
Abstract

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.

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