6MDB

Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor Pyrazolo-pyrimidinone 5

Summary for 6MDB

• Entry DOI: 10.2210/pdb6mdb/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: shp2, ptpn11, protein tyrosine phosphatase, phosphatase, allosteric inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 121769.58

Authors

Fodor, M.,Stams, T. (deposition date: 2018-09-04, release date: 2019-02-13, Last modification date: 2023-10-11)

Primary citation

Sarver, P.,Acker, M.,Bagdanoff, J.T.,Chen, Z.,Chen, Y.N.,Chan, H.,Firestone, B.,Fodor, M.,Fortanet, J.,Hao, H.,Hentemann, M.,Kato, M.,Koenig, R.,LaBonte, L.R.,Liu, G.,Liu, S.,Liu, C.,McNeill, E.,Mohseni, M.,Sendzik, M.,Stams, T.,Spence, S.,Tamez, V.,Tichkule, R.,Towler, C.,Wang, H.,Wang, P.,Williams, S.L.,Yu, B.,LaMarche, M.J.
6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors.
J. Med. Chem., 62:1793-1802, 2019

PubMed Abstract: Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. We also report other pyrimidinone analogues with favorable pharmacokinetic and potency profiles. Overall, this work improves upon our previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism.

PubMed: 30688459
DOI: 10.1021/acs.jmedchem.8b01726

Experimental method

X-RAY DIFFRACTION (2.34 Å)