7JVN
Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor Compound 24
Summary for 7JVN
| Entry DOI | 10.2210/pdb7jvn/pdb |
| Descriptor | Tyrosine-protein phosphatase non-receptor type 11, 6-(4-amino-4-methylpiperidin-1-yl)-3-[(2,3-dichlorophenyl)sulfanyl]pyrazin-2-amine, PHOSPHATE ION, ... (4 entities in total) |
| Functional Keywords | phosphatase ptp, inhibitor, ptpn11, allosteric, shp2, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 121929.37 |
| Authors | |
| Primary citation | LaMarche, M.J.,Acker, M.,Argintaru, A.,Bauer, D.,Boisclair, J.,Chan, H.,Chen, C.H.,Chen, Y.N.,Chen, Z.,Deng, Z.,Dore, M.,Dunstan, D.,Fan, J.,Fekkes, P.,Firestone, B.,Fodor, M.,Garcia-Fortanet, J.,Fortin, P.D.,Fridrich, C.,Giraldes, J.,Glick, M.,Grunenfelder, D.,Hao, H.X.,Hentemann, M.,Ho, S.,Jouk, A.,Kang, Z.B.,Karki, R.,Kato, M.,Keen, N.,Koenig, R.,LaBonte, L.R.,Larrow, J.,Liu, G.,Liu, S.,Majumdar, D.,Mathieu, S.,Meyer, M.J.,Mohseni, M.,Ntaganda, R.,Palermo, M.,Perez, L.,Pu, M.,Ramsey, T.,Reilly, J.,Sarver, P.,Sellers, W.R.,Sendzik, M.,Shultz, M.D.,Slisz, J.,Slocum, K.,Smith, T.,Spence, S.,Stams, T.,Straub, C.,Tamez Jr., V.,Toure, B.B.,Towler, C.,Wang, P.,Wang, H.,Williams, S.L.,Yang, F.,Yu, B.,Zhang, J.H.,Zhu, S. Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer. J.Med.Chem., 63:13578-13594, 2020 Cited by PubMed Abstract: SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent antitumor activity. These studies culminated in the discovery of TNO155, (3,4)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer. PubMed: 32910655DOI: 10.1021/acs.jmedchem.0c01170 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.917 Å) |
Structure validation
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