Isoprenylcysteine carboxylmethyltransferase as a target for development of novel cancer therapeutics
Isoprenylcysteine carboxylmethyltransferase (lcmt), which catalyzes the last step of the three-step post-translational modification of a group of proteins containing the so-called CaaX motif, has become the focus of research in the quest for discovering new and more effective cancer therapies, lcmt is the only enzyme that performs carboxyl methylation of isoprenoid-modified proteins, termed prenyl proteins, and hence is of crucial importance in this processing pathway. Substrates of lcmt include not only most members of the well-known Ras GTPase superfamily of proteins, but also a host of other proteins that have functional roles in important aspects of biological regulation. Efforts to assess the impact of lcmt inhibition on tumorigenesis in particular increased after protein farnesyltransferase inhibitors (FTIs) performed below expectation in solid tumors. A selective small-molecule inhibitor of lcmt termed cysmethynil has recently been described which significantly inhibits transformed cell growth and triggers cell death. The precise mechanisms by which lcmt inhibition results in antiproliferative responses, in particular which of its many substrates are involved, remain unclear and are presently being examined. Inhibitors of lcmt have the potential not only for the treatment of cancer, but also other diseases related to aberrant function of CaaX proteins, including inflammatory diseases such as rheumatoid arthritis. Copyright © 2006 Prous Science.
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