Recent Progress in Developing Small Molecule Inhibitors Designed to Interfere with Ras Membrane Association

Tamanoi, Fuyuhiko; Lü, Jie

doi:10.1016/b978-0-12-420146-0.00008-1

Cited by 11 publications

(11 citation statements)

References 45 publications

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“…As it was quickly determined to be both an obligate modification for oncogenic RAS biological activity and a process governed by an enzyme that recognized a simple short tetrapeptide CAAX motif, this step was rapidly exploited for inhibition. Both rational drug design and library screening were employed in numerous intensive and successful efforts to identify FTase inhibitors (FTIs) (16,17). Two of these, lonafarnib and tipifarnib, progressed to advanced clinical trials but failed to show efficacy against KRAS-driven cancers (16,17).…”

Section: Targeting Caax Prenylation: Ftase and Ggtase Statinsmentioning

confidence: 99%

“…Both rational drug design and library screening were employed in numerous intensive and successful efforts to identify FTase inhibitors (FTIs) (16,17). Two of these, lonafarnib and tipifarnib, progressed to advanced clinical trials but failed to show efficacy against KRAS-driven cancers (16,17). The failure of FTIs, once anticipated to bemagic bullets for RAS-driven cancers, to serve as broadly effective anti-RAS drugs led to a widespread misperception that even RAS itself is not a good target.…”

Section: Targeting Caax Prenylation: Ftase and Ggtase Statinsmentioning

confidence: 99%

“…One potential solution to the problem of alternative prenylation might be dual inhibition of FTase and GGTase I (20), either by combining individual inhibitors of each enzyme, or by dual specificity inhibitors. Such inhibitors have been developed and some have reached the clinic (16,17), but have been limited by toxicity (21-23). There are still hopes that a therapeutic window can be found, possibly by targeting their delivery to RAS-driven cancer cells (17), where oncogenic RAS rendered cytosolic by these agents could sequester effectors and act as dominant negatives (24,25).…”

Section: Targeting Caax Prenylation: Ftase and Ggtase Statinsmentioning

confidence: 99%

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

Cox

Der

Philips

2015

Clinical Cancer Research

323

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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Section: Targeting Caax Prenylation: Ftase and Ggtase Statinsmentioning

confidence: 99%

Section: Targeting Caax Prenylation: Ftase and Ggtase Statinsmentioning

confidence: 99%

Section: Targeting Caax Prenylation: Ftase and Ggtase Statinsmentioning

confidence: 99%

See 1 more Smart Citation

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

Cox

Der

Philips

2015

Clinical Cancer Research

323

292

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“…(6). Kobe 0065 was selected for its ability to inhibit the binding of H-Ras-GTP to Ras-Raf-binding domains (Shima et al, 2013). pathway in antitumor drug treatment mainly include directly targeting Ras proteins, inhibiting processes related to translation or modification, and inhibiting the downstream molecules of the Ras-Related signaling pathway (Tamanoi and Lu, 2013;Cox et al, 2014). Thus, the Ras-Related signaling pathway represents a new direction for developing effective and accurate antitumor drugs, and research on antitumor drugs based on Ras is crucial.…”

Section: Introductionmentioning

confidence: 99%

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

Chen

Zhu

et al. 2020

Front. Pharmacol.

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The Ras-Related signaling pathway plays an important role in cell development and differentiation. A growing body of evidence collected in recent years has shown that the aberrant activation of Ras is associated with tumor-related processes. Several studies have indicated that indole and its derivatives can target regulatory factors and interfere with or even block the aberrant Ras-Related pathway to treat or improve malignant tumors. In this review, we summarize the roles of indole and its derivatives in the isoprenylcysteine carboxyl methyltransferase-participant Ras membrane localization signaling pathway and Ras-GTP/Raf/MAPK signaling pathway through their regulatory mechanisms. Moreover, we briefly discuss the current treatment strategies that target these pathways. Our review will help guide the further study of the application of Ras-Related signaling pathway inhibitors.

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“…Numerous inhibitors of FTase were developed to target this modification and inhibit K-RAS addressing to the membrane(153,154). The non-peptidomimetic competitive FTI, Tipifarnib (R115777), was tested in phase III trials in pancreatic cancer(155,156) but was ineffective because of an unexpected alternative prenylation mechanism (geranylgeranylation) involving geranylgeranyl transferase (GGTase)(157). GGT-I can recognize the CAAL motif and geranylates K-RAS4B.…”

mentioning

confidence: 99%

The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting

Jonckheere

Vasseur

Seuningen

2017

Critical Reviews in Oncology/Hematology

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RAS belongs to the super family of small G proteins and plays crucial roles in signal transduction from membrane receptors in the cell. Mutations of K-RAS oncogene lead to an accumulation of GTP-bound proteins that maintains an active conformation. In the pancreatic ductal adenocarcinoma (PDAC), one of the most deadly cancers in occidental countries, mutations of the K-RAS oncogene are nearly systematic (>90%). Moreover, K-RAS mutation is the earliest genetic alteration occurring during pancreatic carcinogenetic sequence. In this review, we discuss the central role of K-RAS mutations and their tremendous diversity of biological properties by the interconnected regulation of signaling pathways (MAPKs, NF-κB, PI3K, Ral…). In pancreatic ductal adenocarcinoma, transcriptome analysis and preclinical animal models showed that K-RAS mutation alters biological behavior of PDAC cells (promoting proliferation, migration and invasion, evading growth suppressors, regulating mucin pattern, and miRNA expression). K-RAS also impacts tumor microenvironment and PDAC metabolism reprogramming. Finally we discuss therapeutic targeting strategies of K-RAS that have been developed without significant clinical success so far. As K-RAS is considered as the undruggable target, targeting its multiple effectors and target genes should be considered as potential alternatives.

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Recent Progress in Developing Small Molecule Inhibitors Designed to Interfere with Ras Membrane Association

Cited by 11 publications

References 45 publications

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

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

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

The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting

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