2. Academic Validation
  3. Discovery of tetrahydroisoquinolineindole derivatives as first dual PRMT5 inhibitors/hnRNP E1 upregulators: Design, synthesis and biological evaluation

Discovery of tetrahydroisoquinolineindole derivatives as first dual PRMT5 inhibitors/hnRNP E1 upregulators: Design, synthesis and biological evaluation

  • Eur J Med Chem. 2023 Oct 5;258:115625. doi: 10.1016/j.ejmech.2023.115625.
Wen-Hui Chu 1,  Na Yang 2,  Jin-He Zhang 1,  Yue Li 1,  Jia-Li Song 1,  Zhi-Peng Deng 3,  Ning Meng 4,  Juan Zhang 5,  Kong-Kai Zhu 6,  Cheng-Shi Jiang 7
Affiliations

Affiliations

  • 1 School of Biological Science and Technology, University of Jinan, Jinan, 250022, China.
  • 2 School of Biological Science and Technology, University of Jinan, Jinan, 250022, China; Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 3 College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250355, China.
  • 4 School of Biological Science and Technology, University of Jinan, Jinan, 250022, China. Electronic address: mls_mengn@ujn.edu.cn.
  • 5 School of Biological Science and Technology, University of Jinan, Jinan, 250022, China. Electronic address: bio_zhangj@ujn.edu.cn.
  • 6 Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: hkhhh.k@163.com.
  • 7 School of Biological Science and Technology, University of Jinan, Jinan, 250022, China. Electronic address: bio_jiangcs@ujn.edu.cn.
PMID: 37429083 DOI: 10.1016/j.ejmech.2023.115625
Abstract

Protein arginine methyltransferase 5 (PRMT5) is an Epigenetics related Enzyme that has been validated as an important therapeutic target for treating various types of Cancer. Upregulation of tumor suppressor hnRNP E1 has also been considered as an effective antitumor therapy. In this study, a series of tetrahydroisoquinolineindole hybrids were designed and prepared, and compounds 3m and 3s4 were found to be selective inhibitors of PRMT5 and upregulators of hnRNP E1. Molecular docking studies indicated that compounds 3m occupied the substrate site of PRMT5 and formed essential interactions with amino acid residues. Furthermore, compounds 3m and 3s4 exerted antiproliferative effects against A549 cells by inducing Apoptosis and inhibiting cell migration. Importantly, silencing of hnRNP E1 eliminated the antitumor effect of 3m and 3s4 on the Apoptosis and migration in A549 cells, suggesting a regulatory relationship between PRMT5 and hnRNP E1. Additionally, compound 3m exhibited high metabolic stability on human liver microsomes (T1/2 = 132.4 min). In SD rats, the bioavailability of 3m was 31.4%, and its PK profiles showed satisfactory AUC and Cmax values compared to the positive control. These results suggest that compound 3m is the first class of dual PRMT5 Inhibitor and hnRNP E1 upregulator that deserves further investigation as a potential Anticancer agent.

Keywords

Anticancer; Molecular docking; PK profiles; PRMT5 inhibitor; Tetrahydroisoquinolineindole hybrids; hnRNP E1 promoter.

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