Lipidic inhibitors of human N-myristoyltransferase

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 IC50 values were <1 muM, between 1 and 100 muM or >100 muM in eight, four and seven compounds, respectively. Of the six myristoyl-CoA analogs, five had IC50 values in the 0.06-0.59 muM range. These molecules were examined using three additional substrates viz pp60(src), 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

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