7UW6

The co-crystal structure of low molecular weight protein tyrosine phosphatase (LMW-PTP) with a small molecule inhibitor SPAA-2

Summary for 7UW6

• Entry DOI: 10.2210/pdb7uw6/pdb
• Descriptor: Low molecular weight phosphotyrosine protein phosphatase, 2-[(1,3-benzothiazol-2-yl)amino]-2-oxoethane-1-sulfonic acid (3 entities in total)
• Functional Keywords: low molecular weight protein tyrosine phosphatase; inhibitor; complex, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 20377.98

Authors

Wang, J.,Zhang, Z.Y. (deposition date: 2022-05-02, release date: 2022-10-19, Last modification date: 2023-10-18)

Primary citation

He, R.,Wang, J.,Yu, Z.H.,Moyers, J.S.,Michael, M.D.,Durham, T.B.,Cramer, J.W.,Qian, Y.,Lin, A.,Wu, L.,Noinaj, N.,Barrett, D.G.,Zhang, Z.Y.
Structure-Based Design of Active-Site-Directed, Highly Potent, Selective, and Orally Bioavailable Low-Molecular-Weight Protein Tyrosine Phosphatase Inhibitors.
J.Med.Chem., 65:13892-13909, 2022

PubMed Abstract: Protein tyrosine phosphatases constitute an important class of drug targets whose potential has been limited by the paucity of drug-like small-molecule inhibitors. We recently described a class of active-site-directed, moderately selective, and potent inhibitors of the low-molecular-weight protein tyrosine phosphatase (LMW-PTP). Here, we report our extensive structure-based design and optimization effort that afforded inhibitors with vastly improved potency and specificity. The leading compound inhibits LMW-PTP potently and selectively ( = 1.2 nM, >8000-fold selectivity). Many compounds exhibit favorable drug-like properties, such as low molecular weight, weak cytochrome P450 inhibition, high metabolic stability, moderate to high cell permeability (Papp > 0.2 nm/s), and moderate to good oral bioavailability (% from 23 to 50% in mice), and therefore can be used as in vivo chemical probes to further dissect the complex biological as well as pathophysiological roles of LMW-PTP and for the development of therapeutics targeting LMW-PTP.

PubMed: 36197449
DOI: 10.1021/acs.jmedchem.2c01143

Experimental method

X-RAY DIFFRACTION (1.5 Å)