ISDA: 9ZMG

Deposition Date 2025-12-10

Release Date 2026-05-27

Last Version Date 2026-05-27

Entry Detail

PDB ID:

9ZMG

Keywords:

HYDROLASE/INHIBITOR

Title:

Structure of PTP1b complexed with difluoromethylphosphonate inhibitor Compound 15

Biological Source:

Source Organism(s):

Homo sapiens (Taxon ID: 9606)

Expression System(s):

Escherichia coli bl21(de3)

Method Details:

Experimental Method:

X-RAY DIFFRACTION

Resolution:

2.15 Å

R-Value Free:

0.25

R-Value Work:

0.20

R-Value Observed:

0.20

Space Group:

P 31 2 1

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Macromolecular Entities

Structures with similar UniProt ID

Protein Blast

Polymer Type:polypeptide(L)
Molecule:Tyrosine-protein phosphatase
Gene (Uniprot):PTPN1
Chain IDs:A
Chain Length:333
Number of Molecules:1
Biological Source:Homo sapiens

UniProt ID:P18031 Pfam ID:PF00102 EC:3.1.3.48

Ligand Molecules

A1C3C

DMS

Primary Citation

Discovery of Potent and Selective Benzothiophene Difluoromethyl Phosphonate (DFMP) PTPN2/N1-Dual Inhibitors.

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.Show

J.Med.Chem. 69 10515 10530 (2026)

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

Abstact

PTPN1 and PTPN2 are interesting targets for immuno-oncology due to their ability to modulate IFNgamma 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 25 exhibited good potency, high selectivity, favorable PK, and dose-dependent pSTAT1 induction in a MC38 mouse model. These results establish compound 25 as promising structurally differentiated tool to study PTPN1/N2 inhibition and underscore the importance of SLC19A1 in the transport of DFMPs.

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Primary Citation of related structures

Abstact

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