Inhibiting the “Undruggable” RAS/Farnesyltransferase (FTase) Cancer Target by Manumycin-related Natural Products

2021 ◽  
Vol 28 ◽  
Author(s):  
Leandro Rocha Silva ◽  
Edeildo Ferreira da Silva-Júnior
Keyword(s):  
Natural Products ◽  
Anticancer Agents ◽  
Cysteine Residue ◽  
Ras Proteins ◽  
Post Translational Modification ◽  
Promising Alternative ◽  
Ras Genes ◽  
Human Cancers ◽  
Ras Family ◽  
The Face

: Cancer is an uncontrolled cell growth that can generate diverse types of cancer, in which these will also present a different behavior in the face of pharmacological treatment. These cancers’ types are found in one of the three categories, leukemias (also named lymphomas), carcinomas, and sarcomas. In general, cancer's pathogenesis is associated with three genetic mutations, where could emerge from oncogenes, tumor suppressor genes, and/or genes responsible for regulating DNA replication. The term “undruggable” is frequently related to the difficulty to design drugs to specific targets, such as MYC, MYB, NF-κB, and RAS family of proteins. This last comprises more than 140 proteins, and these are responsible for 30% of mutations in human cancers. Also, there are three ras genes transcribed in human cells, called H-, K-, and N-ras oncogenes. Still, the RAS proteins (farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase) enzymes) perform essential steps in post-translational modification of eukaryotes cells, such as (1) the farnesylation of the cysteine residue at the C-terminal tetrapeptide CAAX; (2) proteolytic cleavage of the three C-terminal AAX oligopeptide; and (3) carboxymethylation of the new C-terminal prenylated cysteine. Thus, the inhibition of this undruggable RAS family of proteins has been considered a promising alternative to design new anticancer agents since they are responsible for many types of human cancers. Then, the manumycin A (obtained from the Streptomyces parvulus Tü64) and its analogs (epoxyquinol core with or without their southern and eastern side chains; and dihydroxycyclohexenones core) have been described as promising FTase inhibitors, which have demonstrated their benefits against several types of cancer. In this review, a complete introduction about cancer and its relation with RAS proteins is provided, as well as, the prenylation mechanism of the cysteine residue is discussed in detail. Posteriorly, studies involving manumycin-related compounds are described, showing some synthetic routes for obtaining them and utilizing these natural products in monotherapies or combined therapies with other anticancer drugs.

scholarly journals RAS genes in colorectal carcinoma: pathogenesis, testing guidelines and treatment implications

2018 ◽  
Vol 72 (2) ◽  
pp. 135-139 ◽  
Author(s):  
Omer Saeed ◽  
Antonio Lopez-Beltran ◽  
Kurt W Fisher ◽  
Marina Scarpelli ◽  
Rodolfo Montironi ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Colorectal Carcinoma ◽  
Growth Factor Receptor ◽  
Membrane Receptors ◽  
Metastatic Colon Cancer ◽  
Ras Proteins ◽  
Ras Mutations ◽  
Ras Genes ◽  
Ras Family ◽  
Immunotherapy Study

The RAS family is among the most commonly mutated genes in all human malignancies including colon cancer. In normal cells, RAS proteins act as a link in the intracellular signal transduction initiated by binding of growth factors to cell membrane receptors mediating cell survival. RAS isoproteins have great morphological similarities, but despite that, they are thought to have different functions in different tissues. RAS mutations, as supported by several studies including animal models, have a role in the development and progression of colorectal cancer. The detection of RAS mutations in patients with colorectal carcinoma, specifically KRAS and NRAS, has significant clinical implications. It is currently recommended that patients with colon cancer who are considered for antiepidermal growth factor receptor monoclonal antibodies, get RAS mutation testing since only those with wildtype-RAS genes benefit from such treatment. Despite decades of research, there is currently no effective and safe treatment that directly targets RAS-mutated neoplasms. Multiple therapeutic approaches directed against RAS mutations are currently experimental, including a promising immunotherapy study using T-cells in patients with metastatic colon cancer.

scholarly journals SIRT2 and lysine fatty acylation regulate the oncogenic activity of K-Ras4a

2017 ◽  
Author(s):  
Hui Jing ◽  
Xiaoyu Zhang ◽  
Stephanie A. Wisner ◽  
Xiao Chen ◽  
Nicole A. Spiegelman ◽  
...  
Keyword(s):  
Regulatory Mechanism ◽  
Splice Variants ◽  
Biological Significance ◽  
Cellular Transformation ◽  
Biological Processes ◽  
Ras Proteins ◽  
Post Translational Modification ◽  
Fatty Acylation ◽  
Ras Family ◽  
Cell Signaling Pathways

AbstractRas proteins play vital roles in numerous biological processes and Ras mutations are found in many human tumors. Understanding how Ras proteins are regulated is important for elucidating cell signaling pathways and identifying new targets for treating human diseases. Here we report that one of the K-Ras splice variants, K-Ras4a, is subject to lysine fatty acylation, a previously under-studied protein post-translational modification. Sirtuin 2 (SIRT2), one of the mammalian nicotinamide adenine dinucleotide (NAD)-dependent lysine deacylases, catalyzes the removal of fatty acylation from K-Ras4a. We further demonstrate that SIRT2-mediated lysine defatty-acylation promotes endomembrane localization of K-Ras4a, enhances its interaction with A-Raf, and thus promotes cellular transformation. Our study identifies lysine fatty acylation as a previously unknown regulatory mechanism for the Ras family of GTPases that is distinct from cysteine fatty acylation. These findings highlight the biological significance of lysine fatty acylation and sirtuin-catalyzed protein lysine defatty-acylation.

scholarly journals SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Hui Jing ◽  
Xiaoyu Zhang ◽  
Stephanie A Wisner ◽  
Xiao Chen ◽  
Nicole A Spiegelman ◽  
...  
Keyword(s):  
Splice Variants ◽  
Biological Significance ◽  
Cellular Transformation ◽  
Biological Processes ◽  
Ras Proteins ◽  
Post Translational Modification ◽  
Fatty Acylation ◽  
Ras Family ◽  
Transforming Activity ◽  
Cell Signaling Pathways

Ras proteins play vital roles in numerous biological processes and Ras mutations are found in many human tumors. Understanding how Ras proteins are regulated is important for elucidating cell signaling pathways and identifying new targets for treating human diseases. Here we report that one of the K-Ras splice variants, K-Ras4a, is subject to lysine fatty acylation, a previously under-studied protein post-translational modification. Sirtuin 2 (SIRT2), one of the mammalian nicotinamide adenine dinucleotide (NAD)-dependent lysine deacylases, catalyzes the removal of fatty acylation from K-Ras4a. We further demonstrate that SIRT2-mediated lysine defatty-acylation promotes endomembrane localization of K-Ras4a, enhances its interaction with A-Raf, and thus promotes cellular transformation. Our study identifies lysine fatty acylation as a previously unknown regulatory mechanism for the Ras family of GTPases that is distinct from cysteine fatty acylation. These findings highlight the biological significance of lysine fatty acylation and sirtuin-catalyzed protein lysine defatty-acylation.

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine Suppresses the Plasma Membrane Translocation and Neoplastic Transforming Activity of NRAS and KRAS4A

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 434-434
Author(s):  
Min Wu ◽  
Bo Jiao ◽  
Ruibao Ren
Keyword(s):  
Plasma Membrane ◽  
Transformed Cells ◽  
Specific Cell ◽  
Ras Proteins ◽  
Membrane Translocation ◽  
Homologous Proteins ◽  
Ras Genes ◽  
Human Cancers ◽  
New Findings ◽  
Transforming Activity

Abstract The RAS family includes three RAS genes, which encode four highly homologous proteins: H-, N-, and KRAS4A and 4B, the latter two being alternatively spliced forms differing only at the carboxyl terminus. RAS oncogenic mutations, mostly KRAS and NRAS, are common in human cancers. Since the enzymatic activity of RAS is used to turn itself off and its GTP binding affinity is very high, RAS proteins have been difficult to target. Identification of alternative means to block the RAS oncogenic signaling is critical for developing therapies against RAS-driven cancer. We took a chemical biology approach to discover novel therapeutic strategies for RAS-related cancer. Since the biological activity of RAS proteins relies upon lipid modifications and RAS regulates lipid metabolisms in cancer cells, we used a RAS specific cell viability assay to screen a bioactive lipid library for potential therapeutics against RAS-driven cancer. We found that endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) could effectively kill RAS-transformed cells. The structure-activity analysis showed that the anti-RAS activity of NADA relied on both the dopamine and arachidonoyl moieties in the same molecule and was independent of its ability to engage cannabinoid or vanilloid receptors. Further analysis showed that NADA was more active in killing cells transformed by oncogenic NRAS or KRAS4A than that of KRAS4B. Consistently, NADA was more active in inhibiting the phosphorylation of ERK in NRAS-transformed cells than that in KRAS4B-transformed cells. Interestingly, NADA blocked the plasma membrane translocation of NRAS and KRAS4A, but not that of KRAS4B. Significant effect of NADA on palmitoylated NRAS levels was not detected, suggesting that NADA inhibits NRAS and KRAS4A plasma membrane translocation through a novel mechanism. These results demonstrate that NADA possesses a novel property of inhibiting the plasma membrane translocation and neoplastic transforming activity of NRAS and KRAS4A. Since NRAS mutations are common in hematological malignancies as well as in solid tumors such as melanoma and colorectal carcinoma, and KRAS4A is required for carcinogen-induced lung cancer, the new findings would help to develop novel therapies for a broad range of human cancers. Disclosures No relevant conflicts of interest to declare.

scholarly journals Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1037 ◽  
Author(s):  
Cho ◽  
Kim ◽  
Baek ◽  
Kim ◽  
Lee
Keyword(s):  
Cell Migration ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Regulatory Mechanisms ◽  
Malignant Phenotype ◽  
Cellular Processes ◽  
Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

scholarly journals Antioxidant potential and optimization of production of extracellular polysaccharide by Acinetobacter indicus M6

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ch. Ravi Teja ◽  
Abraham P. Karlapudi ◽  
Neeraja Vallur ◽  
K. Mamatha ◽  
D. John Babu ◽  
...  
Keyword(s):  
Antioxidant Activities ◽  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Basal Medium ◽  
Extracellular Polysaccharide ◽  
Extracellular Polysaccharides ◽  
Scavenging Activity ◽  
Promising Alternative ◽  
Food Engineering ◽  
The Face

Abstract Background Extracellular polysaccharides (ECPs) produced by biofilm-producing marine bacterium have great applications in biotechnology, pharmaceutical, food engineering, bioremediation, and bio-hydrometallurgy industries. The ECP-producing strain was identified as Acinetobacter indicus M6 species by 16S rDNA analysis. The polymer produced by the isolate was quantified and purified and chemically analyzed, and antioxidant activities have been studied. The face-centered central composite design (FCCCD) was used to design the model. Results The results have clearly shown that the ECP was found to be endowed with significant antioxidative activities. The ECP showed 59% of hydroxyl radical scavenging activity at a concentration of 500 μg/mL, superoxide radical scavenging activity (72.4%) at a concentration of 300 μg/mL, and DPPH˙ radical scavenging activity (72.2%) at a concentration of 500 μg/mL, respectively. Further, HPLC and GC-MS results showed that the isolated ECP was a heteropolymer composed of glucose as a major monomer, and mannose and glucosamine were minor monomers. Furthermore, the production of ECP by Acinetobacter indicus M6 was increased through optimization of nutritional variables, namely, glucose, yeast extract, and MgSO4 by “Response Surface Methodology”. Moreover the production of ECP reached to 2.21 g/L after the optimization of nutritional variables. The designed model is statistically significant and is indicated by the R2 value of 0.99. The optimized medium improved the production of ECP and is two folds higher in comparison with the basal medium. Conclusions Acinetobacter indicus M6 bacterium produces a novel and unique extracellular heteropolysaccharide with highly efficient antioxidant activity. GC-MS analyses elucidated the presence of quite uncommon (1→4)-linked glucose, (1→4)-linked mannose, and (→4)-GlcN-(1→) glycosidic linkages in the backbone. The optimized medium improved the production of ECP and is two folds higher in comparison with the basal medium. The newly optimized medium could be used as a promising alternative for the overproduction of ECP.

scholarly journals Structures ofDrosophila melanogasterRab2 and Rab3 bound to GMPPNP

2015 ◽  
Vol 71 (1) ◽  
pp. 34-40 ◽  
Author(s):  
Jennifer A. Lardong ◽  
Jan H. Driller ◽  
Harald Depner ◽  
Christoph Weise ◽  
Astrid Petzoldt ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Intracellular Trafficking ◽  
Large Family ◽  
Cysteine Residue ◽  
Effector Proteins ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Ras Proteins ◽  
Transport Vesicles ◽  
Switch Regions

Rab GTPases belong to the large family of Ras proteins. They act as key regulators of membrane organization and intracellular trafficking. Functionally, they act as switches. In the active GTP-bound form they can bind to effector proteins to facilitate the delivery of transport vesicles. Upon stimulation, the GTP is hydrolyzed and the Rab proteins undergo conformational changes in their switch regions. This study focuses on Rab2 and Rab3 fromDrosophila melanogaster. Whereas Rab2 is involved in vesicle transport between the Golgi and the endoplasmatic reticulum, Rab3 is a key player in exocytosis, and in the synapse it is involved in the assembly of the presynaptic active zone. Here, high-resolution crystal structures of Rab2 and Rab3 in complex with GMPPNP and Mg2+are presented. In the structure of Rab3 a modified cysteine residue is observed with an enigmatic electron density attached to its thiol function.

Recent Advances on Small Molecule Medicinal Chemistry to Treat Human Diseases-Part III

2021 ◽  
Vol 21 (17) ◽  
pp. 1517-1518
Author(s):  
Dharmendra Kumar Yadav
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Small Molecule ◽  
Anticancer Agents ◽  
Medicinal Chemistry ◽  
Review Article ◽  
Human Diseases ◽  
Bioactive Metabolite ◽  
Metabolite Production ◽  
Life Threatening

The discovery and utilization of novel metabolites from natural sources are gaining momentum in the present era. The drug discovery programs have witnessed a remarkable shift from conventional medicines to exploiting natural products and their “value addition”, for treating lifethreatening diseases. The global outbreak of life-threatening diseases namely Ebola, SARS,including infections of the bloodstream (bacteremia), heart valves (endocarditis), lungs (pneumonia), and brain (meningitis) and AIDS calls for a more targeted approach to effectively combat the emerging diseases. In the present scenario, natural products and their extracts are being explored extensively for the treatment of various life threatening diseases. In this thematic issue, several review articles contributed by the scientist and researchers in the different areas of medicinal chemistry, synthetic chemistry, new emerging multi-drug targets were collected. This issue begins with a review article on the “Chemistry and Pharmacology of Natural Catechins from Camellia sinensis as anti-MRSA agents” by Gaur et al. and focuses on the spread of MRSA strains is of great concern because of limited treatment options for staphylococcal infections, since these strains are resistant to the entire class of β-lactam antibiotics. In addition, MRSA exhibits resistance to other classes of antimicrobial agents such as fluoroquinolones, cephalosporins, aminoglycosides, macrolide and even glycopeptides (vancomycin and teicoplanine), leading to the emergence of resistant strains such as glycopeptide intermediate (GISA) and resistant strain (GRSA) of S. aureus. In this review, chemical constituents responsible for the anti-MRSA activity of tea are explored [1]. The next article of this issue is a review article on the “Recent Advancements in the Synthesis and Chemistry of Benzofused Nitrogen- and Oxygen-based Bioactive Heterocycles” by Sharma et al. which focuses on medicinal importance of these bioactive benzo-fused heterocycles; special attention has been given to their synthesis as well as medicinal/pharmaceutical properties in detail [2]. “Trends in pharmaceutical design of Endophytes as anti-infective,” by Tiwari et al., is the third article in this issue. The review focused on the meta-analysis of bioactive metabolite production from endophytes, extensively discussing the bioprospection of natural products for pharmaceutical applications. In light of the emerging importance of endophytes as antiinfective agents, an exploration of the pharmaceutical design of novel chemical entities and analogues has enabled efficient and cost-effective drug discovery programs. However, bottlenecks in endophytic biology and research requires a better understanding of endophytic dynamics and mechanism of bioactive metabolite production towards a sustainable drug discovery program [3]. The last article of this issue is also research article on “Recent development of tetrahydro-quinoline/isoquinoline based compounds as anticancer agents” by Yadav et al. The article reported the synthesis of potent tetrahydroquinoline/isoquinoline molecules of the last 10 years with their anticancer properties in various cancer cell lines and stated their half-maximal inhibitory concentration (IC50). In addition, we also considered the discussion of molecular docking and structural activity relationship wherever provided to understand the possible mode of activity an target involved and structural features responsible for the better activity, so the reader can directly find detail for designing new anticancer agents. [4]. Finally I would like to thank all authors who contributed to this issue, titled “Recent advances on small molecule medicinal chemistry to treat human diseases”.

Semisynthetic triazoles as an approach in the discovery of Novel Lead Compounds

2021 ◽  
Vol 25 ◽  
Author(s):  
Pedro Alves Bezerra Morais ◽  
Carla Santana Francisco ◽  
Heberth de Paula ◽  
Rayssa Ribeiro ◽  
Mariana Alves Eloy ◽  
...  
Keyword(s):  
Natural Products ◽  
Medicinal Chemistry ◽  
Chemical Space ◽  
Biological Activities ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Modern Drug ◽  
New Chemical Entities ◽  
Almost All ◽  
The 19Th Century

: Historically, the medicinal chemistry is concerned with the approach of organic chemistry to new drug synthesis. Considering the fruitful collections of new molecular entities, the dedicated efforts for medicinal chemistry are rewarding. Planning and search of new and applicable pharmacologic therapies involve the altruistic nature of the scientists. Since the 19th century, notoriously the application of isolated and characterized plant-derived compounds in modern drug discovery and in various stages of clinical development highlight its viability and significance. Natural products influence a broad range of biological processes, covering transcription, translation, and post-translational modification and being effective modulators of almost all basic cellular processes. The research of new chemical entities through “click chemistry” continuously opens up a map for the remarkable exploration of chemical space in towards leading natural products optimization by structure-activity relationship. Finally, here in this review, we expect to gather a broad knowledge involving triazolic natural products derivatives, synthetic routes, structures, and their biological activities.

Ras proteins as therapeutic targets

2018 ◽  
Vol 46 (5) ◽  
pp. 1303-1311 ◽  
Author(s):  
Atanu Chakraborty ◽  
Emily Linnane ◽  
Sarah Ross
Keyword(s):  
Therapeutic Strategies ◽  
Targeted Therapeutics ◽  
Ras Proteins ◽  
Ras Genes ◽  
Small Molecule Drug ◽  
Oncogenic Mutations ◽  
Recent Developments ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic ◽  
Made In

Oncogenic mutations in RAS genes underlie the pathogenesis of many human tumours, and there has been intense effort for over 30 years to develop effective and tolerated targeted therapeutics for patients with Ras-driven cancers. This review summarises the progress made in Ras drug discovery, highlighting some of the recent developments in directly targeting Ras through advances in small molecule drug design and novel therapeutic strategies.

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