An overview on natural farnesyltransferase inhibitors for efficient cancer therapy

Dai, Xianzhong; Sun, Yingni; Zhang, Ting; Ming, Yongfei; Gao, Hongwei

doi:10.1080/14756366.2020.1732366

Cited by 15 publications

(13 citation statements)

References 137 publications

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“…To identify useful natural products, numerous isoprenoids are of significant commercial value owing to their broad-spectrum clinical and industrial applications (Tables 1 and 2). 19,[128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145] At present, the screening, isolation, and identification of new forms of natural compounds with pharmacological properties have gained increasing attention in academia and industry. In recent preclinical and clinical studies, the number of newly identified natural products with therapeutic efficacy in humans against diseases such as cancer, hepatitis, osteoporosis, and respiratory tract diseases has rapidly increased.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, some of these inhibitors have been assessed in clinical trials. 24,[128][129][130][131][132] Another natural cyclic monoterpenoid, limonene, a major component of fruit-derived essential oils, is a flavoring agent in food manufacturing. Research on its D-form isomer, dlimonene, has progressed to phase one clinical studies for breast, parotid, and submandibular gland cancers (Figure 8c, Tables 1 and 2).…”

Section: Structural and Functional Analysesmentioning

confidence: 99%

“…Over the past few years, numerous analogs, including natural isoprenoids, have been synthesized or extracted and subsequently used in investigations into various aspects of the prenylation reaction including its mechanisms, protein structures, enzyme kinetics, and prenylated proteomes. Moreover, some of these inhibitors have been assessed in clinical trials 24,128–132 . Wu et al extracted natural terpenoid antroquinonols from Antrodia camphorate , 133 which may inhibit the activity of FTase and GGTase in cancer cells; in turn, this may inhibit the function of Ras and Ras‐related GTP‐binding proteins.…”

Section: Class 6: Protein Prenylationmentioning

confidence: 99%

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Structure, catalysis, and inhibition mechanism of prenyltransferase

Chang¹,

Cheng²,

Wang

2020

IUBMB Life

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Isoprenoids, also known as terpenes or terpenoids, represent a large family of natural products composed of five-carbon isopentenyl diphosphate or its isomer dimethylallyl diphosphate as the building blocks. Isoprenoids are structurally and functionally diverse and include dolichols, steroid hormones, carotenoids, retinoids, aromatic metabolites, the isoprenoid side-chain of ubiquinone, and isoprenoid attached signaling proteins. Productions of isoprenoids are catalyzed by a group of enzymes known as prenyltransferases, such as farnesyltransferases, geranylgeranyltransferases, terpenoid cyclase, squalene synthase, aromatic prenyltransferase, and cis-and trans-prenyltransferases. Because these enzymes are key in cellular processes and metabolic pathways, they are expected to be potential targets in new drug discovery. In this review, six distinct subsets of characterized prenyltransferases are structurally and mechanistically classified, including (1) head-to-tail prenyl synthase, (2) head-to-head prenyl synthase, (3) head-tomiddle prenyl synthase, (4) terpenoid cyclase, (5) aromatic prenyltransferase, and (6) protein prenylation. Inhibitors of those enzymes for potential therapies against several diseases are discussed. Lastly, recent results on the structures of integral membrane enzyme, undecaprenyl pyrophosphate phosphatase, are also discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Structural and Functional Analysesmentioning

confidence: 99%

Section: Class 6: Protein Prenylationmentioning

confidence: 99%

See 1 more Smart Citation

Structure, catalysis, and inhibition mechanism of prenyltransferase

Chang¹,

Cheng²,

Wang

2020

IUBMB Life

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“…Specific farnesyl transferase (FTase) inhibitors were developed, but this strategy collided with the activity of geranylgeranyl transferase (GGTase), allowing an alternative way for Ras targeting to the membranes [ 13 ]. Several natural products interfering either with the mevalonate pathway or with farnesyl transferase activity itself were characterized (for reviews, see [ 161 , 162 ]). Here, we summarize some compounds among the more efficient against cancer cell proliferation recently characterized ( Table 2 ).…”

Section: Natural Products Targeting Biosynthesis Processing and mentioning

confidence: 99%

Natural Products Attenuating Biosynthesis, Processing, and Activity of Ras Oncoproteins: State of the Art and Future Perspectives

et al. 2020

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RAS genes encode signaling proteins, which, in mammalian cells, act as molecular switches regulating critical cellular processes as proliferation, growth, differentiation, survival, motility, and metabolism in response to specific stimuli. Deregulation of Ras functions has a high impact on human health: gain-of-function point mutations in RAS genes are found in some developmental disorders and thirty percent of all human cancers, including the deadliest. For this reason, the pathogenic Ras variants represent important clinical targets against which to develop novel, effective, and possibly selective pharmacological inhibitors. Natural products represent a virtually unlimited resource of structurally different compounds from which one could draw on for this purpose, given the improvements in isolation and screening of active molecules from complex sources. After a summary of Ras proteins molecular and regulatory features and Ras-dependent pathways relevant for drug development, we point out the most promising inhibitory approaches, the known druggable sites of wild-type and oncogenic Ras mutants, and describe the known natural compounds capable of attenuating Ras signaling. Finally, we highlight critical issues and perspectives for the future selection of potential Ras inhibitors from natural sources.

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“…Natural products are known sources of lead compounds, and a host of natural inhibitors of FTase have been reported [6]. The anticancer potentials of ascorbic acid have been reported [7].…”

Section: Introductionmentioning

confidence: 99%

vHTS and 3D-QSAR for the Identification of Novel Phyto-inhibitors of Farnesyltransferase: Validation of Ascorbic Acid inhibition of Farnesyltransferase in an Animal Model of Breast Cancer

Metibemu

2021

Drug Res (Stuttg)

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Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of attention in anti-cancer research over the past. In this study, phytochemicals from Curcuma longa L., Taraxacum officinale, and Spondias mombin plants were screened for their inhibitory potentials on the human farnesyltransferase. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model for the inhibition of farnesyltransferase was generated and the inhibition of farnesyltransferase by the hit, ascorbic acid was validated in an animal model of breast cancer. The lead compound, ascorbic acid makes extensive hydrogen bond interactions with key residues, lys-353, tyr-300, gly-290, leu-290 within the active site of farnesyltransferase. It downregulated the expression of FNTA mRNA in an animal model of breast cancer. The 3D-QSAR generated herein is robust, thoroughly validated, and should be employed in the pipelining of novel farnesyltransferase inhibitors. Ascorbic acid demonstrates its anticancer potentials through the inhibition of farnesyltransferase.

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An overview on natural farnesyltransferase inhibitors for efficient cancer therapy

Cited by 15 publications

References 137 publications

Structure, catalysis, and inhibition mechanism of prenyltransferase

Structure, catalysis, and inhibition mechanism of prenyltransferase

Natural Products Attenuating Biosynthesis, Processing, and Activity of Ras Oncoproteins: State of the Art and Future Perspectives

vHTS and 3D-QSAR for the Identification of Novel Phyto-inhibitors of Farnesyltransferase: Validation of Ascorbic Acid inhibition of Farnesyltransferase in an Animal Model of Breast Cancer

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