Depsidones from Lichens as Natural Product Inhibitors of M-Phase Phosphoprotein 1, a Human Kinesin Required for Cytokinesis.
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.
Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University College London , 29-39 Brunswick Square, London WC1N 1AX, U.K.|The Beatson Institute for Cancer Research , Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, U.K.
Sandeep K
SK
Talapatra
The Beatson Institute for Cancer Research , Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, U.K.
Oliver
O
Rath
Cyprotex Discovery Ltd , 15 Beech Lane, Macclesfield, Cheshire SK10 2DR, U.K.
Eddie
E
Clayton
Equipe PNSCM "Produits Naturels - Synthèses - Chimie Médicinale", Unités Mixtes de Recherche, Centre National de la Recherche Scientifique, 6226 Sciences Chimiques de Rennes, UFR Sciences Pharmaceutiques et Biologiques, Univ. Rennes 1, Université Bretagne Loire , 2 Avenue du Pr. Léon Bernard, F-35043 Rennes, France.
Sophie
S
Tomasi
Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University College London , 29-39 Brunswick Square, London WC1N 1AX, U.K.
Frank
F
Kozielski
D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols; D048749:Cytokinesis / Q000187:drug effects; D053630:Depsides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D003990:Dibenzoxepins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D008011:Lichens / Q000737:chemistry*; D008558:Melphalan; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D011241:Prednisone; D011344:Procarbazine
D053630:Depsides; D003990:Dibenzoxepins; D007783:Lactones; C000618531:norlobaridone; C000875:depsidone; D011344:Procarbazine; C438388:KIF20B protein, human; D016547:Kinesins; D008558:Melphalan; D011241:Prednisone; C043056:physodic acid