Design and structural requirements of potent peptidomimetic inhibitors of p21ras farnesyltransferase.

Qian, Yimin; Blaskovich, Michelle A.; Saleem, Muhammad; Seong, Churl Min; Wathen, S. P.; Hamilton, Andrew D.; Sebti, Saı̈d M.

doi:10.1016/s0021-9258(18)99888-1

Cited by 116 publications

(49 citation statements)

References 26 publications

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“…Preliminary strategies were directed towards CAAX tetrapeptide inhibitors, which were competitive with the protein substrate [ 14 ]. However, such tetrapeptides were not efficiently taken up into cells, and the drug discovery efforts shifted toward more stable, peptidomimetic inhibitors [ 15 , 16 , 17 , 18 ]. Small molecule inhibitors were identified through high-throughput screening efforts and aided by crystallographic structures [ 19 ].…”

Section: Tipifarnib In Hras-mutant Hnscc—history Preclinical Validation and Clinical Developmentmentioning

confidence: 99%

Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas

Kessler

Malik

Leoni

et al. 2021

Cancers

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Current therapies for recurrent and metastatic SCC are associated with poor outcomes, and options for later lines of treatment are limited. Insights into potential therapeutic targets, as well as mechanisms of resistance to available therapies, have begun to be elucidated, creating the basis for exploration of combination approaches to drive better patient outcomes. Tipifarnib, a farnesyl transferase inhibitor (FTI), is a small molecule drug that has demonstrated encouraging clinical activity in a genetically-defined subset of head and neck squamous cell carcinoma (HNSCC)–specifically, tumors that express a mutation in the HRAS protooncogene. More recently, bioinformatic analyses and results from patient-derived xenograft modeling indicate that HRAS pathway dependency may extend to a broader subpopulation of SCCs beyond HRAS mutants in the context of combination with agents such as cisplatin, cetuximab, or alpelisib. In addition, tipifarnib can also inactivate additional farnesylated proteins implicated in resistance to approved therapies, including immunotherapies, through a variety of distinct mechanisms, suggesting that tipifarnib could serve as an anchor for combination regimens in SCCs and other tumor types.

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Section: Tipifarnib In Hras-mutant Hnscc—history Preclinical Validation and Clinical Developmentmentioning

confidence: 99%

Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas

Kessler

Malik

Leoni

et al. 2021

Cancers

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“…In one example, a methyl ester derivative of the tetrapeptide, CVIM (the KRAS4b C-terminus), inhibited delivery of RAS to the membrane and activation of MAPK signaling (Lerner et al, 1995). In addition, a number of non-peptide mimetics of the CaaX motif proved to be "true" FTIs in that they were not modified or inactivated by FTase (Nigam et al, 1993;Qian et al, 1994;Vogt et al, 1995), and restored normal growth patterns to RAS-transformed cells (James et al, 1993). A number of these compounds even showed preclinical efficacy in RAS-driven models of pancreatic cancer (Kohl et al, 1994), lung cancer (Sun et al, 1995), and breast cancer (Kohl et al, 1995).…”

Section: Inhibition Of Ras Prenylation-rasmentioning

confidence: 99%

Biology, pathology, and therapeutic targeting of RAS

Rhett

Khan

O’Bryan

2020

Advances in Cancer Research

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RAS was identified as a human oncogene in the early 1980's and found to be mutated in nearly 30% of all human cancers. More importantly, however, RAS plays a central role in driving tumor development and maintenance. Despite decades of effort, there remain no FDA approved drugs that directly inhibit RAS. The prevalence of RAS mutations in cancer and the lack of effective anti-RAS therapies stem from RAS' core role in growth factor signaling, unique structural features, and biochemistry. However, recent advances have brought promising new drugs to clinical trials and shone a ray of hope in the field. Here, we will exposit the details of RAS biology that illustrate its key role in cell signaling and shed light on the difficulties in therapeutically targeting RAS. Furthermore, past and current efforts to develop RAS inhibitors will be discussed in depth.

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“…Similar scaffolds have been successfully incorporated within the structures of Src SH2 domain antagonists, 10 growth hormone-releasing peptide receptor agonists 11 and Ras farnesyl protein transferase inhibitors. 12 These isosteres introduce rigidity and hydrophobicity to the system as well as reducing the total amide bond content. We replaced the Val-Thr unit with a variety of spacers that incorporated 3-or 4-aminobenzoic acid and 3-or 4-aminomethylbenzoic acid.…”

Section: Design and Synthesis Of Inhibitorsmentioning

confidence: 99%

Peptides to peptidomimetics: towards the design and synthesis of bioavailable inhibitors of oligosaccharyl transferase

Weerapana

Imperiali

2002

Org. Biomol. Chem.

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Oligosaccharyl transferase (OT) is the enzyme responsible for asparagine-linked glycosylation in the lumen of the endoplasmic reticulum, which is a subcellular compartment within eukaryotic cells. Inhibition of this enzyme within a cellular environment would provide a valuable investigative tool for glycobiology. Due to the limitations of peptides, none of the existing peptide-based inhibitors of OT demonstrate activity in cell-based enzyme assays. We report herein the design, synthesis and preliminary biological characterization of a family of peptidomimetics that inhibit OT with Ki values in the nanomolar range. The hexapeptide Bz-Dab-Ala-Thr-Val-Thr-Nph-NH2 (Ki = 69 nM) was used as the prototype for the design of bioavailable inhibitors. Several aminobenzoic acid spacer groups were evaluated as potential isosteres of the Val-Thr dipeptide unit and the peptidomimetic incorporating 3-aminobenzoic acid proved to inhibit OT with similar potency to the parent compound (Ki = 84 nM). Further modifications explored the effects of size, hydrophobicity and conformational rigidity on enzyme affinity. This study yielded a family of potent non-peptidic inhibitors that are viable candidates for the in vivo inhibition of OT.

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Design and structural requirements of potent peptidomimetic inhibitors of p21ras farnesyltransferase.

Cited by 116 publications

References 26 publications

Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas

Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas

Biology, pathology, and therapeutic targeting of RAS

Peptides to peptidomimetics: towards the design and synthesis of bioavailable inhibitors of oligosaccharyl transferase

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