2. Academic Validation
  3. Identification of novel GSPT1 degraders by virtual screening and bioassay

Identification of novel GSPT1 degraders by virtual screening and bioassay

  • Eur J Med Chem. 2024 Jul 5:273:116524. doi: 10.1016/j.ejmech.2024.116524.
Shuqun Zhang 1,  Shiyun Nie 2,  Guangchao Ma 2,  Meiling Shen 3,  Lingmei Kong 2,  Zhili Zuo 4,  Yan Li 5
Affiliations

Affiliations

  • 1 Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
  • 2 Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, China.
  • 3 Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: zuozhili@mail.kib.ac.cn.
  • 5 Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, China. Electronic address: yan.li@ynu.edu.cn.
PMID: 38795517 DOI: 10.1016/j.ejmech.2024.116524
Abstract

GSPT1 plays crucial physiological functions, such as terminating protein translation, overexpressed in various tumors. It is a promising anti-tumor target, but is also considered as an "undruggable" protein. Recent studies have found that a class of small molecules can degrade GSPT1 through the "molecular glue" mechanism with strong antitumor activity, which is expected to become a new therapy for hematological malignancies. Currently available GSPT1 degraders are mostly derived from the scaffold of immunomodulatory imide drug (IMiD), thus more active compounds with novel structure remain to be found. In this work, using computer-assisted multi-round virtual screening and bioassay, we identified a non-IMiD acylhydrazone compound, AN5782, which can reduce the protein level of GPST1 and obviously inhibit the proliferation of tumor cells. Some analogs were obtained by a substructure search of AN5782. The structure-activity relationship analysis revealed possible interactions between these compounds and CRBN-GSPT1. Further biological mechanistic studies showed that AN5777 decreased GSPT1 remarkably through the ubiquitin-proteasome system, and its effective cytotoxicity was CRBN- and GSPT1-dependent. Furthermore, AN5777 displayed good antiproliferative activities against U937 and OCI-AML-2 cells, and dose-dependently induced G1 phase arrest and Apoptosis. The structure found in this work could be good start for antitumor drug development.

Keywords

Antitumor; CRBN; GSPT1; Molecular glue; Virtual screening.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-161696
    GSPT1 降解剂
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