19730-75-7Relevant academic research and scientific papers
SAR of non-hydrolysable analogs of pyridoxal 5′-phosphate against low molecular weight protein tyrosine phosphatase isoforms
DeSouza, Shirin R.,Flynn, Rebecca S.,Jakubowski, Henry V.,Marshall, Quinlen F.,McIntee, Edward J.,Olson, Maxwell C.,Sinner, Erica K.,Tinucci, Samantha L.
, (2020/07/21)
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 Kis 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.
Synthesis of hydrolysis-resistant pyridoxal 5′-phosphate analogs and their biochemical and X-ray crystallographic characterization with the pyridoxal phosphatase chronophin
Knobloch, Gunnar,Jabari, Nauras,Stadlbauer, Sven,Schindelin, Hermann,K?hn, Maja,Gohla, Antje
, p. 2819 - 2827 (2015/03/30)
A set of phosphonic acid derivatives (1-4) of pyridoxal 5′-phosphate (PLP) was synthesized and characterized biochemically using purified murine pyridoxal phosphatase (PDXP), also known as chronophin. The most promising compound 1 displayed primarily competitive PDXP inhibitory activity with an IC50 value of 79 μM, which was in the range of the Km of the physiological substrate PLP. We also report the X-ray crystal structure of PDXP bound to compound 3, which we solved to 2.75 ? resolution (PDB code 5AES). The co-crystal structure proves that compound 3 binds in the same orientation as PLP, and confirms the mode of inhibition to be competitive. Thus, we identify compound 1 as a PDXP phosphatase inhibitor. Our results suggest a strategy to design new, potent and selective PDXP inhibitors, which may be useful to increase the sensitivity of tumor cells to treatment with cytotoxic agents.
