Identification of novel GSPT1 degraders by virtual screening and bioassay

doi:10.1016/j.ejmech.2024.116524

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	Identification of novel GSPT1 degraders by virtual screening and bioassay
	Zhang, Shuqun; Nie, Shiyun; Ma, Guangchao; Shen, Meiling; Kong, Lingmei; Zuo, Zhili; Li, Yan
	2024
发表期刊	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN	0223-5234
卷号	273 页码:116524
摘要	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 multiround 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.
DOI	10.1016/j.ejmech.2024.116524
WOS记录号	WOS:001246277200001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/76350
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Zhang, Shuqun,Nie, Shiyun,Ma, Guangchao,et al. Identification of novel GSPT1 degraders by virtual screening and bioassay[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,273:116524.
APA	Zhang, Shuqun.,Nie, Shiyun.,Ma, Guangchao.,Shen, Meiling.,Kong, Lingmei.,...&Li, Yan.(2024).Identification of novel GSPT1 degraders by virtual screening and bioassay.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,273,116524.
MLA	Zhang, Shuqun,et al."Identification of novel GSPT1 degraders by virtual screening and bioassay".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 273(2024):116524.

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