An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo

Abstract

Inhibitors of isoprenylcysteine carboxylmethyltransferase (Icmt) are promising anti-cancer agents, as modification by Icmt is an essential component of the protein prenylation pathway for a group of proteins that includes Ras GTPases. Cysmethynil, a prototypical indole-based inhibitor of Icmt, effectively inhibits tumor cell growth. However, the physical properties of cysmethynil, such as its low aqueous solubility, make it a poor candidate for clinical development. A novel amino-derivative of cysmethynil with superior physical properties and marked improvement in efficacy, termed compound 8.12, has recently been reported. We report here that Icmt (-/-) mouse embryonic fibroblasts (MEFs) are much more resistant to compound 8.12-induced cell death than their wild-type counterparts, providing evidence that the anti-proliferative effects of this compound are mediated through an Icmt specific mechanism. Treatment of PC3 prostate and HepG2 liver cancer cells with compound 8.12 resulted in pre-lamin A accumulation and Ras delocalization from the plasma membrane, both expected outcomes from inhibition of the Icmt-catalyzed carboxylmethylation. Treatment with compound 8.12 induced cell cycle arrest, autophagy and cell death, and abolished anchorage-independent colony formation. Consistent with its greater in vitro efficacy, compound 8.12 inhibited tumor growth with greater potency than cysmethynil in a xenograft mouse model. Further, a drug combination study identified synergistic antitumor efficacy of compound 8.12 and the epithelial growth factor receptor (EGFR)-inhibitor gefitinib, possibly through enhancement of autophagy. This study establishes compound 8.12 as a pharmacological inhibitor of Icmt that is an attractive candidate for further preclinical and clinical development.

Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

“…Disappointingly, even the most potent and selective of the RCE1 inhibitors have recently been shown to lack mechanism-based activity (43). The anti-proliferative effects of ICMT inhibitors on RAS-transformed cells may be more compelling (41,42); whether they can be converted into pharmacological leads is currently unclear.…”

Mutational Analysis of the Integral Membrane Methyltransferase Isoprenylcysteine Carboxyl Methyltransferase (ICMT) Reveals Potential Substrate Binding Sites

“…A recent report that knocking out ICMT in a mouse model of pancreatic cancer exacerbated the disease (15) underscores the need for further studies exploring the potential utility of ICMT inhibitors. To date, only a few inhibitors of ICMT have been identified, and no clinical trials using these inhibitors have been conducted (13,16,17). The development of effective ICMT inhibitors will benefit from a detailed understanding of the active site of the enzyme.…”

Regulation of the Ras-Related Signaling Pathway by Small Molecules Containing an Indole Core Scaffold: A Potential Antitumor Therapy

“…Although its IC50-Icmt inhibition value is 7.7 ± µM and its IC50-antiproliferative activity is 28.5 ± 5.3 µM, its SlogP value is 4.9. These results indicate that if the R3 position have an appropriate amino groups, the chains with low lipophilicity will improved activities in Icmt inhibition and cell growth inhibition (Lau et al, 2014).…”