5EHP

Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor SHP836

Summary for 5EHP

• Entry DOI: 10.2210/pdb5ehp/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 5-[2,3-bis(chloranyl)phenyl]-2-[(3~{R},5~{S})-3,5-dimethylpiperazin-1-yl]pyrimidin-4-amine, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: phosphatase ptp inhibitor ptpn11 allosteric, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q06124
• Total number of polymer chains: 2
• Total formula weight: 122134.36

Authors

Stams, T.,Fodor, M. (deposition date: 2015-10-28, release date: 2016-07-06, Last modification date: 2023-09-27)

Primary citation

Garcia Fortanet, J.,Chen, C.H.,Chen, Y.N.,Chen, Z.,Deng, Z.,Firestone, B.,Fekkes, P.,Fodor, M.,Fortin, P.D.,Fridrich, C.,Grunenfelder, D.,Ho, S.,Kang, Z.B.,Karki, R.,Kato, M.,Keen, N.,LaBonte, L.R.,Larrow, J.,Lenoir, F.,Liu, G.,Liu, S.,Lombardo, F.,Majumdar, D.,Meyer, M.J.,Palermo, M.,Perez, L.,Pu, M.,Ramsey, T.,Sellers, W.R.,Shultz, M.D.,Stams, T.,Towler, C.,Wang, P.,Williams, S.L.,Zhang, J.H.,LaMarche, M.J.
Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor.
J.Med.Chem., 59:7773-7782, 2016

PubMed Abstract: SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.

PubMed: 27347692
DOI: 10.1021/acs.jmedchem.6b00680

Experimental method

X-RAY DIFFRACTION (1.85 Å)