Structural highlights
FunctionPPAC_HUMAN Acts on tyrosine phosphorylated proteins, low-MW aryl phosphates and natural and synthetic acyl phosphates. Isoform 3 does not possess phosphatase activity. Publication Abstract from PubMedProtein 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 (Ki = 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 (% F 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. Structure-Based Design of Active-Site-Directed, Highly Potent, Selective, and Orally Bioavailable Low-Molecular-Weight Protein Tyrosine Phosphatase Inhibitors.,He R, Wang J, Yu ZH, Moyers JS, Michael MD, Durham TB, Cramer JW, Qian Y, Lin A, Wu L, Noinaj N, Barrett DG, Zhang ZY J Med Chem. 2022 Oct 5. doi: 10.1021/acs.jmedchem.2c01143. PMID:36197449[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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