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Depsidones from Lichens as Natural Product Inhibitors of M-Phase Phosphoprotein 1, a Human Kinesin Required for Cytokinesis

Talapatra, SK; Rath, O; Clayton, E; Tomasi, S; Kozielski, F; (2016) Depsidones from Lichens as Natural Product Inhibitors of M-Phase Phosphoprotein 1, a Human Kinesin Required for Cytokinesis. Journal of Natural Products , 79 (6) pp. 1576-1585. 10.1021/acs.jnatprod.5b00962. Green open access

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Abstract

M-Phase Phosphoprotein 1 (MPP1), a microtubule plus end directed kinesin, is required for the completion of cytokinesis. Previous studies have shown that MPP1 is upregulated in various types of bladder cancer. This article describes inhibitor screening leading to the identification of a new class of natural product inhibitors of MPP1. Two compounds with structural similarity, norlobaridone (1) and physodic acid (2), were found to inhibit MPP1. Physodic acid is not competitive with ATP, indicating the presence of an allosteric inhibitor-binding pocket. Initial drug-like property screening indicates that physodic acid is more soluble than norlobaridone and has more favorable lipophilicity. However, both suffer from high clearance in human microsomal stability assays mediated by the lability of the lactone ring as well as hydroxylation of the alkyl chains as shown by metabolite identification studies. In cell-based assays physodic acid is a weak inhibitor with EC50 values of about 30 μM in a range of tumor cell lines. The two depsidones identified and characterized here could be used for future improvement of their activity against MPP1 and will be useful chemical probes for studying this unique molecular motor in more depth.

Type: Article
Title: Depsidones from Lichens as Natural Product Inhibitors of M-Phase Phosphoprotein 1, a Human Kinesin Required for Cytokinesis
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.jnatprod.5b00962
Publisher version: http://dx.doi.org/10.1021/acs.jnatprod.5b00962
Language: English
Additional information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Natural Products, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see: http://dx.doi.org/10.1021/acs.jnatprod.5b00962.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > SoP Pharmaceutical and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1499913
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