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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A number of different ways to inhibit FTase have been proposed. For example, one approach is to make use of the “CAAX” motif to simulate the C-terminal tetrapeptide and compete with Ras for the farnesylation process. Inhibitors have been made based on simple variations of these amino acids, such as Cys-Val-Phe-Met, which produced compounds with in vitro IC50 values in the 25 nM region. Although short peptides of this type are not very efficient at crossing cell membranes and can be rapidly degraded by hydrolysis in vivo, this approach eventually produced inhibitors with in vitroIC50 values in the 0.7 nM region (e.g., BMS-214662). Farnesyl pyrophosphate analogs have also been considered but have significantly lower activities and are, in general, less attractive because they are competitive in other enzymatic pathways. Other types of inhibitors have been designed that incorporate a farnesyl and CAAX mimetics, and these have enhanced selectivity and potency still further.
Mevalonic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The pathway is regulated via feedback inhibition by cholesterol of the synthesis of mevalonic acid at the 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase step. When cholesterol, which is ingested or derived from plasma low-density lipoproteins (LDL), downregulates HMG CoA reductase, nonsterol isoprenoid synthesis is preserved by inhibition of squalene synthetase and more distal enzymes, further limiting the incorporation of farnesylpyrophosphate into cholesterol. The initial enzymes in the nonsterol branches of the pathway have a very high affinity for farnesylpyrophosphate [26, 27].
Synthetic Approaches to Inhibitors of Isoprenoid Biosynthesis
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Pedro Merino, Loredana Maiuolo, Ignacio Delso, Vincenzo Algieri, Antonio De Nino, Tomas Tejero
The union of compounds 5–7 to the active site of human farnesyl pyrophosphate synthase is 38 to 54 kcal/mol energetically more favorable than the union of the natural substrate (Fernandez et al., 2017). The effects due to presence of chiral groups on BPs was studied by substitution of methylene group linked to pyridine of risedronate with a cyclopentyl ring to confer rigidity to the molecule (Deprele et al., 2008). This chiral derivative was prepared starting from 3-benzyloxybenzaldehyde (16) which was transformed into carboxylic acid (18) by a multistep sequence.
The Effects of Sterol-Related Signaling Pathways on Glioma
Published in Nutrition and Cancer, 2022
Masoumeh Eslahi, Parisa Maleki Dana, Fatemeh Sadoughi, Jamal Hallajzadeh, Zatollah Asemi, Mehran Sharifi, Mohammad Ali Mansournia, Bahman Yousefi
Based on several experimental studies on colon and prostate cancer, phytosterols have been suggested as anti-carcinogenic compounds (20,21). Sterols have different functions such as controlling the fluidity of membrane and permeability. A specific function of sterols has been observed in the proliferation of cell and signal transduction in some plants. Besides, they modulate the activity of membrane-bound enzymes (19). One of the most important features of cellular growth is the sustained production of lipids. The biochemical and biophysical properties of membrane-based processes such as vesicle traffic, receptor signaling, and assembly of protein complexes are highly dependent on the sterol composition of cellular membranes (22). Findings according to the profiling of cancer tissues (23) and in vitro cell line models have shown that cholesterol metabolism has a critical role in the origins of cancer as well as drug resistance (24). Mevalonic acid, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate are essential for cell growth and division and produced in the early steps of cholesterol biosynthesis. Cancer cells highly depend on isoprenylated molecules for cell growth. Several experiments have shown that they target the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA-reductase) with statins and prenylation enzymes as well as farnesyl transferase inhibitor (25). Contrary to the normal differentiated tissues of the nervous system, brain tumors exhibit a high rate of de novo sterol synthesis.
Use of zoledronic acid in antiosteoporosis treatment is associated with a decreased blood lipid level in postmenopausal women with osteoporosis: a cohort study in China
Published in Postgraduate Medicine, 2022
Wei Luo, Jin Zhang, Ling Xu, Yao Zhou, Dan Xu, Qiuju Lv, Yi Xiao, Qin Yang
Osteoporosis, a metabolic bone disease, may coexist with other metabolic diseases, such as, obesity, diabetes, and dyslipidemia. This coexistence can be attributed to the common pathogenetic mechanisms or even cross-talk between these conditions and osteoporosis might also exist [6,7]. Menopausal transition also affects the cardiovascular system and body composition with differences in lipid profile. In a hypoestrogenic state, such as postmenopausal status, the level of low-density lipoprotein cholesterol (LDL-C) increases and the level of high-density lipoprotein cholesterol (HDL-C) decreases [8, 9]. Studies have shown that the bone mineral density (BMD) is negatively correlated with serum lipid levels (total cholesterol (TC) and LDL-C) in postmenopausal women [8, 9]. Hyperlipidemia and associated lipid disorders are considered the major causes of cerebrovascular diseases, stroke, atherosclerotic cardiovascular diseases, and ischemic heart disease [9]. Farnesyl pyrophosphate synthase (FPPS) is a key enzyme that plays an important role in the mevalonate pathway and is responsible for cholesterol synthesis [10,11].
An evidence-based review of neuronal cholesterol role in dementia and statins as a pharmacotherapy in reducing risk of dementia
Published in Expert Review of Neurotherapeutics, 2021
Siddhartha Dutta, Sayeeda Rahman, Rahnuma Ahmad, Tarun Kumar, Gitashree Dutta, Sudeshna Banerjee, Abdullahi Rabiu Abubakar, Adekunle Babajide Rowaiye, Sameer Dhingra, Velayutham Ravichandiran, Santosh Kumar, Paras Sharma, Mainul Haque, Jaykaran Charan
In vitro and animal studies have also shown a crucial role of statins in AD therapy [166]. In support of the mechanism of statin action on APP, it is postulated that it significantly reduces the levels of Aβ 42 and Aβ 40 in vitro and in vivo experiments [167]. Statins also block the synthesis of mevalonate and consequently the production of its isoprenoid derivatives, such as farnesyl pyrophosphate and geranyl pyrophosphate (Figure 3). Farnesyl pyrophosphate and geranyl pyrophosphate, respectively, modulate the farnesylation and geranylation of various proteins such as the GTPases, Rho, and Rab proteins [156]. The post-translational modification of cell-signaling proteins, such as Ras and Rho might affect the neurons’ metabolic activity and amyloid standard processing [168,169].