Discovery and SAR of Methylated Tetrahydropyranyl Derivatives as Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase (ICMT)

Judd, W. R.; Slattum, Paul M.; Hoang, Khanh; Bhoite, Leena; Valppu, Liisa; Alberts, Glen L; Brown, Bryan P.; Roth, Bruce L.; Ostanin, Kirill; Huang, Liwen; Wettstein, Dániel; Richards, Burt; Willardsen, J. Adam

doi:10.1021/jm200249a

Cited by 46 publications

(30 citation statements)

References 30 publications

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“…Thus, strategies that effectively curtail CaaX processing are still considered among the most viable approaches to anti-RAS therapeutics. Accordingly, ICMT is considered a good drug target, and enthusiasm for this approach has been bolstered by several preclinical studies that have found a requirement for ICMT in KRAS-mediated cellular transformation (9) and oncogenesis in vivo (10) as well as in studies suggesting that pharmacologic inhibition of ICMT blocks RAS-dependent transformation (44,45). We set out to solidify this view by studying the role of ICMT in a mouse model of PDA that more faithfully recapitulates human pathology than the cancer models previously examined.…”

Section: Discussionmentioning

confidence: 99%

“…We believe that our results implicate for the first time the Notch pathway as one that must be considered when attempting to predict the pleiotropic effects of ICMT inhibition. Given the fact that in some models, ICMT deficiency ameliorates tumors (10) and that ICMT inhibitors have been shown to have antitumor activity (44,45), does our surprising observation that ICMT deficiency exacerbates KRAS-driven PanINs in one mouse model mean that ICMT inhibitors cannot be developed as drugs? This will depend on how generalized the results are that we report here.…”

Section: Discussionmentioning

confidence: 99%

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Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

Court¹,

Amoyel²,

Hackman³

et al. 2013

J. Clin. Invest.

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RAS is the most frequently mutated oncogene in human cancers. Despite decades of effort, anti-RAS therapies have remained elusive. Isoprenylcysteine carboxylmethyltransferase (ICMT) methylates RAS and other CaaX-containing proteins, but its potential as a target for cancer therapy has not been fully evaluated. We crossed a Pdx1-Cre;LSL-Kras G12D mouse, which is a model of pancreatic ductal adenocarcinoma (PDA), with a mouse harboring a floxed allele of Icmt. Surprisingly, we found that ICMT deficiency dramatically accelerated the development and progression of neoplasia. ICMT-deficient pancreatic ductal epithelial cells had a slight growth advantage and were resistant to premature senescence by a mechanism that involved suppression of cyclin-dependent kinase inhibitor 2A (p16 INK4A ) expression. ICMT deficiency precisely phenocopied Notch1 deficiency in the Pdx1-Cre;LSL-Kras G12D model by exacerbating pancreatic intraepithelial neoplasias, promoting facial papillomas, and derepressing Wnt signaling. Silencing ICMT in human osteosarcoma cells decreased Notch1 signaling in response to stimulation with cell-surface ligands. Additionally, targeted silencing of Ste14, the Drosophila homolog of Icmt, resulted in defects in wing development, consistent with Notch loss of function. Our data suggest that ICMT behaves like a tumor suppressor in PDA because it is required for Notch1 signaling.Introduction RAS is the most frequently mutated oncogene in human cancer (1). This has made RAS the target of drug discovery efforts for more than three decades, but effective anti-RAS therapies have remained elusive (2). RAS is a prototypical small GTPase that functions as a binary molecular switch to regulate a number of signaling pathways including those that control growth and differentiation. RAS is inactive when GDP bound and is active when it binds GTP. The GDP/GTP cycle is controlled by guanine nucleotide exchange factors (GEFs) that activate RAS and by GTPase-activating proteins (GAPs) that dramatically accelerate the rate of GTP hydrolysis catalyzed by RAS, thereby limiting RAS activity (3). The oncogenic mutations found in human cancer are one of several single nucleotide changes in codons 12, 13, or 61 that render RAS insensitive to GAPs and reduce the intrinsic rate of GTP hydrolysis, thus allowing the accumulation of GTP-bound, activated RAS (1, 4). Attempts to devise therapeutic agents that reverse the accumulation of GTP-bound RAS have failed. Accordingly, investigators have taken an alternate approach driven by another hallmark of RAS biology: its regulation of signaling pathways only when associated with cellular membranes (5).RAS is a peripheral membrane protein that gains affinity for membranes as a consequence of a series of posttranslational modifications of a C-terminal CaaX motif (6). The CaaX sequence is first modified by farnesyltransferase (FTase), which adds a farnesyl lipid to the cysteine. Next, RAS-converting enzyme 1 (RCE1) removes the aaX amino acids. Finally, isoprenylcysteine carboxylmethyltransferas...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

Court¹,

Amoyel²,

Hackman³

et al. 2013

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…Thus, even if they can be developed, RCE1 inhibitors may be more toxic overall than ICMT inhibitors. Nevertheless, attempts have been made to develop inhibitors of both RCE1 (39) and ICMT (40-42), although each will necessarily also affect alternate substrates in addition to RAS. Disappointingly, even the most potent and selective of the RCE1 inhibitors have recently been shown to lack mechanism-based activity (43).…”

Section: Targeting Post-prenylation Caax Processing: Rce1 and Icmtmentioning

confidence: 99%

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

Cox

Der

Philips

2015

Clinical Cancer Research

318

292

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RAS proteins require membrane association for their biological activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTIs) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anti-cancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated post-translational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development.

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“…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.…”

mentioning

confidence: 99%

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

Diver

Long

2014

Journal of Biological Chemistry

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Background: Isoprenylcysteine carboxyl methyltransferase (ICMT) is an integral membrane enzyme that modifies CAAX proteins. Results: Mutational analysis has identified residues important for activity and substrate recognition. Conclusion: Crucial residues are found in cytosolic and membrane-embedded regions, consistent with the ability of ICMT to bind both water-soluble and lipophilic substrates. Significance: Insights into the enzymatic mechanism of ICMT may assist with inhibitor development.

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Discovery and SAR of Methylated Tetrahydropyranyl Derivatives as Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase (ICMT)

Cited by 46 publications

References 30 publications

Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

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

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

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