2. Academic Validation
  3. Discovery of novel EGFR-PROTACs capable of degradation of multiple EGFR-mutated proteins

Discovery of novel EGFR-PROTACs capable of degradation of multiple EGFR-mutated proteins

  • Eur J Med Chem. 2024 Jun 5:272:116489. doi: 10.1016/j.ejmech.2024.116489.
Yu Du 1,  Shi Shi 2,  Chen Shu 1,  Yezi He 3,  Wangyang Xu 3,  Daochen Wu 3,  Yushu Tian 3,  Mingyang Kong 3,  Jiahuan He 3,  Wenhui Xie 3,  Yijia Qiu 3,  Yungen Xu 4,  Yi Zou 5,  Qihua Zhu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; Jiangsu Lianhuan Pharmaceutical Co., Ltd, Yangzhou 225000, China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 4 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
PMID: 38759458 DOI: 10.1016/j.ejmech.2024.116489
Abstract

Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13, which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound 13, IV-3 exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI-H1975 cells, and NCI-H1975-TM cells (IC50 = 0.009 μM, 0.49 μM and 3.24 μM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC50 = 17.93 nM, 0.25 μM and 0.63 μM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.

Keywords

EGFR; In vivo efficacy; PROTAC; Xenograft tumors.

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