Discovery of the SHP2 allosteric inhibitor 2-((3R,4R)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(2,3-dichlorophenyl)-3-methylpyrrolo[2,1-f][1,2,4] triazin-4(3H)-one

Autor: Yanmei Luo, Jin Li, Yuliang Zong, Mengxin Sun, Wan Zheng, Jiapeng Zhu, Liu Liu, Bing Liu
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 38, Iss 1, Pp 398-404 (2023)
Druh dokumentu: article
ISSN: 14756366
1475-6374
1475-6366
DOI: 10.1080/14756366.2022.2151594
Popis: The non-receptor protein tyrosine phosphatase (PTP) SHP2 encoded by the PTPN11 gene is a critical regulator in a number of cellular signalling processes and pathways, including the MAPK and the immune-inhibitory programmed cell death PD-L1/PD-1 pathway. Hyperactivation and inactivation of SHP2 is of great therapeutic interest for its association with multiple developmental disorders and cancer-related diseases. In this work, we characterised a potent SHP2 allosteric inhibitor 2-((3 R,4R)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(2,3-dichlorophenyl)-3-methylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (PB17-026-01) by using structure-based design. To study the structure–activity relationship, we compared co-crystal structures of SHP2 bound with PB17-026-01 and its analogue compound PB17-036-01, which is ∼20-fold less active than PB17-026-01, revealing that both of the compounds are bound to SHP2 in the allosteric binding pocket and PB17-026-01 forms more polar contacts with its terminal group. Overall, our results provide new insights into the modes of action of allosteric SHP2 inhibitor and a guide for the design of SHP2 allosteric inhibitor.
Databáze: Directory of Open Access Journals
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