title: Identification of LY83583 as a specific inhibitor of Candida albicans MPS1 protein kinase.
abstract: Candida albicans is the most common and virulent fungus causing candidiasis in various parts of the body and can be lethal to immunocompromised patients. All currently known antifungal therapies are drugs which cause serious side effects in the host. An inhibitor specific for fungus survival is an ideal therapeutic. C. albicans MPS1 (monopolar spindle 1) has been reported as a kinase essential to its survival. Because CaMps1p shares limited sequence homology with the human ortholog (hMps1p), we screened for a chemical inhibitor in anticipation of finding one with Candida specific cytotoxicity. In vitro screening using a recombinant catalytic domain of CaMps1p identified LY83583 (6-anilino-5,8-quinolinedione), known as a guanylate cyclase inhibitor, to be blocking CaMps1p kinase activity. In addition to its in vitro kinase inhibition, LY83583 reduced the growth rate of C. albicans. Finally, we compared the inhibitory activity on CaMps1p and hMps1p among inhibitors against those kinases. LY83583 showed specific inhibition for CaMps1p with no effect on hMps1p activity. Conversely, the CaMps1p activity was not affected by known hMps1p inhibitors. These findings suggest that CaMps1p may well be an ideal target molecule for antifungal therapy.
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy, 2-1-1 Nishitokuta, Yahaba, Shiwa-gun, Iwate 020-3694, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Tsuda
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nishiya
authors.forename: Takashi
authors.initials: T
authors.lastname: Umeyama
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Uehara
mesh_terms: D000634:Aminoquinolines / Q000302:isolation & purification / Q000494:pharmacology*; D000935:Antifungal Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011505:Protein-Tyrosine Kinases
chemical_list: D000634:Aminoquinolines; D000935:Antifungal Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; C041715:6-anilino-5,8-quinolinedione; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human