title: Lipidic inhibitors of human N-myristoyltransferase.
abstract: This study was undertaken in order to identify compounds which inhibit the activity of human myristoyl-CoA:protein N-myristoyltransferase (hNMT). In particular, the structural features of such molecules which contribute to enzyme inhibition were investigated. Two groups of compounds, namely myristic acid and analogs 1-13 and derivatives of myristoyl-CoA 14-19 were evaluated. All compounds were examined using cAMP-dependent protein kinase derived peptide substrate. The IC(50) values were <1 micro M, between 1 and 100 micro M or >100 micro M in eight, four and seven compounds, respectively. Of the six myristoyl-CoA analogs, five had IC(50) values in the 0.06-0.59 micro M range. These molecules were examined using three additional substrates viz pp60src, MARCKS and M2 gene segment of reovirus type 3 which led to results similar to those obtained with the cAMP-dependent protein kinase substrate. On the other hand, evaluation of myristic acid and four related compounds revealed some differences in hNMT-inhibiting properties among the substrates. From the results obtained, the possible manner whereby potent inhibitors interact with the enzyme was formulated thus enabling the design of further analogs as candidate inhibitors of hNMT.
authors.affiliation: Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Mohammed Khysar
authors.initials: MK
authors.lastname: Pasha
authors.forename: Ponniah
authors.initials: P
authors.lastname: Selvakumar
authors.forename: Lakshmikuttyamma
authors.initials: L
authors.lastname: Ashakumary
authors.forename: Mabood
authors.initials: M
authors.lastname: Qureshi
authors.forename: Frank S
authors.initials: FS
authors.lastname: Guziec
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dimmock
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Felsted
authors.forename: Constance J
authors.initials: CJ
authors.lastname: Glover
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Sharma
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D050356:Lipid Metabolism; D008055:Lipids / Q000494:pharmacology; D008954:Models, Biological; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D012087:Reoviridae / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008055:Lipids; D010455:Peptides; D000242:Cyclic AMP; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase; D016392:Proto-Oncogene Proteins pp60(c-src); D017868:Cyclic AMP-Dependent Protein Kinases