7XHQ

Small-molecule Allosteric Regulation Mechanism of SHP2

Summary for 7XHQ

• Entry DOI: 10.2210/pdb7xhq/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 2-[(3S,4R)-4-azanyl-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-[2,3-bis(chloranyl)phenyl]-3-methyl-pyrrolo[2,1-f][1,2,4]triazin-4-one (3 entities in total)
• Functional Keywords: phosphatase, oncoprotein-inhibitor complex, oncoprotein/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 121420.66

Authors

Luo, Y.,Zhu, J.,Yu, K.,Liu, B. (deposition date: 2022-04-09, release date: 2023-02-15, Last modification date: 2024-10-23)

Primary citation

Luo, Y.,Li, J.,Zong, Y.,Sun, M.,Zheng, W.,Zhu, J.,Liu, L.,Liu, B.
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.
J Enzyme Inhib Med Chem, 38:398-404, 2023

PubMed 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.

PubMed: 36476046
DOI: 10.1080/14756366.2022.2151594

Experimental method

X-RAY DIFFRACTION (2.2 Å)