Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
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.
J Med Chem. 2024 Aug 22;67(16):13666-13680. doi: 10.1021/acs.jmedchem.4c00208. Epub 2024 Aug 8.
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: CRL2, 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.
蛋白水解靶向嵌合体（PROTACs）利用泛素-蛋白酶体系统（UPS）选择性地消除有害蛋白，代表了一种针对各种疾病的有前途的治疗策略。降解信号序列和 E3 连接酶的有效适应仍然有限。在这里，我们使用三个氨基酸─甘氨酸（Gly）、脯氨酸（Pro）和赖氨酸（Lys）─作为配体来招募相应的 E3 连接酶：CRL2、GID4 和 UBRs，以降解 NSCLC 中的两种致癌驱动基因 EML4-ALK 和突变型 EGFR。我们发现，通过使用不同的降解信号，可以轻松调整 EML4-ALK 和 EGFR 减少的程度。这些基于氨基酸的 PROTACs，称为 AATacs，可抑制 NSCLC 细胞的体外增殖，并诱导细胞周期停滞和凋亡。与其他 PROTACs 相比，AATacs 体积小、可互换但降解效率不同。我们的研究进一步扩展了 E3 连接酶及其用于 PROTAC 应用的配体的范围，提高了靶向蛋白降解在治疗目的方面的多功能性和实用性。
