Non-Substrate Based, Small Molecule Inhibitors of the Human Isoprenylcysteine Carboxyl Methyltransferase

Activating mutations of human K-Ras proteins are among the most common oncogenic mutations, present in approximately 30% of all human cancers. Posttranslational modifications to K-Ras guide it to the plasma membrane and disruption of this localization inhibits the growth of Ras-driven cancers. The h...

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Published in:MedChemComm 2016-01, Vol.7 (5), p.1016-1021
Main Authors: Butler, Kyle V, Bohn, Kelsey, Hrycyna, Christine A, Jin, Jian
Format: Article
Language:English
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Summary:Activating mutations of human K-Ras proteins are among the most common oncogenic mutations, present in approximately 30% of all human cancers. Posttranslational modifications to K-Ras guide it to the plasma membrane and disruption of this localization inhibits the growth of Ras-driven cancers. The human isoprenylcysteine carboxyl methyltransferase (hIcmt) enzyme catalyzes the final α-carboxyl methylesterification of the C-terminal farnesyl cysteine of K-Ras, which is necessary for its proper localization. Thus, hIcmt inhibition is a regarded as a promising cancer therapy. A high quality inhibitor of hIcmt with activity would advance hIcmt research and drug development. Herein, Wwe report the results of a screen for small molecule hIcmt inhibitors in a library of molecules that were not hIcmt substrate analogs. The lead compound identified by this screen ( ) was modified to remove chemical liabilities and to increase potency. The most potent resulting compound ( ) inhibited hIcmt with low micromolar potency (IC = 1.5 ± 0.2 μM) and was kinetically characterized as a competitive inhibitor for prenylated substrates and a non-competitive inhibitor for the cofactor and methyl donor -adenosylmethionine (SAM). These inhibitors offer important structure activity relationships for the future development of hIcmt inhibitors with activity.
ISSN:2040-2503
2040-2511
DOI:10.1039/c6md00130k