SAR of non-hydrolysable analogs of pyridoxal 5'-phosphate against low molecular weight protein tyrosine phosphatase isoforms

Shirin R DeSouza; Maxwell C Olson; Samantha L Tinucci; Erica K Sinner; Rebecca S Flynn; Quinlen F Marshall; Henry V Jakubowski; Edward J McIntee

doi:10.1016/j.bmcl.2020.127342

SAR of non-hydrolysable analogs of pyridoxal 5'-phosphate against low molecular weight protein tyrosine phosphatase isoforms

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127342. doi: 10.1016/j.bmcl.2020.127342. Epub 2020 Jun 10.

Authors

Shirin R DeSouza¹, Maxwell C Olson¹, Samantha L Tinucci¹, Erica K Sinner¹, Rebecca S Flynn¹, Quinlen F Marshall¹, Henry V Jakubowski¹, Edward J McIntee²

Affiliations

¹ Department of Chemistry, College of Saint Benedict, Saint John's University, St. Joseph, MN 56374, United States.
² Department of Chemistry, College of Saint Benedict, Saint John's University, St. Joseph, MN 56374, United States. Electronic address: emcintee@csbsju.edu.

PMID: 32631543
DOI: 10.1016/j.bmcl.2020.127342

Abstract

Kinases and phosphatases are key enzymes in cell signal transduction pathways. Imbalances in these enzymes have been linked to numerous disease states ranging from cancer to diabetes to autoimmune disorders. The two isoforms (IFA and IFB) of Low Molecular Weight Protein Tyrosine Phosphatase (LMW-PTP) appear to play a role in these diseases. Pyridoxal 5'-phosphate (PLP) has been shown to act as a potent but, impractical micromolar inhibitor for both isoforms. In this study, a series of non-hydrolysable phosphonate analogs of PLP were designed, synthesized and tested against the two isoforms of LMW-PTP. Assay results demonstrated that the best inhibitor for both isoforms was compound 5 with a K_is of 1.84 μM (IFA) and 15.6 μM (IFB). The most selective inhibitor was compound 16, with a selectivity of roughly 370-fold for IFA over IFB.

Keywords: Cancer; Drug discovery; Inhibitors; LMW-PTP; SAR.

MeSH terms

Dose-Response Relationship, Drug
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Models, Molecular
Molecular Structure
Molecular Weight
Protein Tyrosine Phosphatases / antagonists & inhibitors*
Protein Tyrosine Phosphatases / metabolism
Pyridoxal Phosphate / chemistry
Pyridoxal Phosphate / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Isoenzymes
Pyridoxal Phosphate
Protein Tyrosine Phosphatases