9ZME

Structure of PTP1b complexed with difluoromethylphosphonate inhibitor Compound 2

This is a non-PDB format compatible entry.

Summary for 9ZME

• Entry DOI: 10.2210/pdb9zme/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 1, {[3-bromo-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]di(fluoro)methyl}phosphonic acid (3 entities in total)
• Functional Keywords: hydrolase-inhibitor complex, ptp1b, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 39322.42

Authors

Palte, R.L.,Schneider, S.E.,Candito, D.A.,Zheng, X.M.,Huang, H.,Stinn, A.,Lindner, I. (deposition date: 2025-12-10, release date: 2026-05-27)

Primary citation

Zheng, X.M.,Candito, D.A.,Jewell, J.,Childers, M.,Kawamura, S.,Logan, K.M.,Otte, R.D.,Yeung, C.S.,Xiao, D.,Liu, P.,DeMong, D.E.,Huang, C.,Sanyal, S.,McGowan, M.,Levi, S.M.,Schneider, S.E.,Fradera, X.,Palte, R.L.,Lyons, T.W.,Poremba, K.E.,Miller, J.R.,Chai, X.,Xu, Z.,Musisi, I.,Mansueto, M.S.,Venkataraman, S.,Moy, L.Y.,Zhang, M.,Yang, Y.,Cheng, M.,McLeod, R.,Laskey, J.,Angagaw, M.,Smith, D.M.,Varkhede, N.,Muise, E.S.,Bass, A.,Walraven, J.,Doty, A.,Yu, H.,Rath, B.,Engstrom, L.,Wang, H.,Follmer, N.E.,Slavonic, M.,Ehrenberger, T.,Nicholson, B.,Haining, W.N.,Bennett, D.J.,DiMauro, E.F.,Machacek, M.R.,Shumway, S.
Discovery of Potent and Selective Benzothiophene Difluoromethyl Phosphonate (DFMP) PTPN2/N1-Dual Inhibitors.
J.Med.Chem., 69:10515-10530, 2026

PubMed Abstract: PTPN1 and PTPN2 are interesting targets for immuno-oncology due to their ability to modulate IFNγ signaling and T-cell activity. We report the discovery of benzothiophene difluoromethyl phosphonate (DFMP) inhibitors with potent dual PTPN1/PTPN2 activity. Structure-based design and a late-stage Ir-catalyzed C-H borylation enabled C5/C7-disubstituted designs that produced a marked inflection in potency. Systematic vector optimization improved potency, selectivity, and pharmacokinetic properties. Mechanistic studies identified SLC19A1 as a key transporter mediating cellular uptake. Lead compound exhibited good potency, high selectivity, favorable PK, and dose-dependent pSTAT1 induction in a MC38 mouse model. These results establish compound as promising structurally differentiated tool to study PTPN1/N2 inhibition and underscore the importance of SLC19A1 in the transport of DFMPs.

PubMed: 42054654
DOI: 10.1021/acs.jmedchem.5c03738

Experimental method

X-RAY DIFFRACTION (1.73 Å)