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. (31st December 2023)

• Record Type: Journal Article
• Authors: Luo, Yanmei; Li, Jin; Zong, Yuliang; Sun, Mengxin; Zheng, Wan; Zhu, Jiapeng; Liu, Liu; Liu, Bing
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 38:Number 1(2023)
• Page Start: 398
• Page End: 404
• Publication Date: 2023-12-31
• Subjects: SHP2 -- allosteric inhibitor -- X-ray crystallography; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2022.2151594
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: 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.