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Farnesyltransferase Inhibitors: Current and Prospective Development for Hematologic Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
With respect to other Ras-related proteins, studies in Caenorhabditis elegans demonstrate that FTIs can induce apoptosis by inhibiting the structurally distinct prenyltransferase enzyme Rab-GGT (GGT type II), which prenylates the Ras-related protein Rab (22). Rab proteins regulate endosomal trafficking and, like Ras, require posttranslational prenylation for membrane attachment and function. FTIs abrogate Rab-GGT activity and thereby directly induce p53-independent apoptosis. In addition, FTIs may exert cytotoxicity by inhibiting farnesylation of the Ras-related protein RHEB (Ras homologue enriched in brain). RHEB inhibition, in turn, blocks downstream mTor/S6 kinase signaling (2,3,23).
Proteins as Trigger Factors of Immediate Skin Contact Reactions
Published in Ana M. Giménez-Arnau, Howard I. Maibach, Contact Urticaria Syndrome, 2014
Paolo Daniele Pigatto, Rossano Hermes Valsecchi
Rubber particles (spherical droplets of chains of cis-1, 4 polyisoprene wrapped in a layer of phospholipoprotein). In 1989, two important proteins were identified and sequenced for the synthesis of cis-1, 4 polyisoprene: the prenyltransferase (38 kDa) that catalyzes the summation of the isoprene units, and the rubber elongation factor (14.6 KDa), a cofactor necessary for the activity of cis-prenyltransferase.
Rational design, optimization, and biological evaluation of novel α-Phosphonopropionic acids as covalent inhibitors of Rab geranylgeranyl transferase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Joanna Małolepsza, Aleksandra Marchwicka, Remigiusz A. Serwa, Sanna P. Niinivehmas, Olli T. Pentikäinen, Edyta Gendaszewska-Darmach, Katarzyna M. Błażewska
Compounds 1–6 were examined for their potency against RGGT, using a procedure previously developed in our group.17 We also tested their selectivity by assessing the prenylation of Rap1A/Rap1B, a substrate of a structurally similar prenyltransferase, GGTase-I. The results were supported by covalent docking studies and the LC-MS-based peptide mapping.
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
In the G1 phase, Cyclin D/CDK4/CDK6-induced phosphorylation inactivates the RBP; leading to the release of RBP from E2F and induction of the S phase in the cell cycle. CDKN2B is commonly inactivated in glioblastoma and acts as an inhibitor of CDK. It forms a complex with CDK4 or CDK6 and thereby, inhibits CDK. Cell growth and cell cycle are prevented by this inhibition through the progression of G1 and maintaining the RBP activation state (76). In addition to CDKN2B inactivation, amplification of CDK4 and CDK6 is also common in this disorder; showing that both CDK4 and CDK6 play pivotal roles in astrocytic tumorigenesis and progression of glioma (77). Since the kinase activity of the CDK4/CDK6/Cyclin D complex inactivates the RBP pathway, it is concluded that the CDK4/6 inhibition may be a novel treatment strategy in glioblastoma patients who aberrantly expressed RBP (63). RB has an important role in the regulation of DNA damage response and senescence of cells by E2F-dependent suppression of N-Ras isoprenylation (78). Furthermore, the inactivation of RBP induces aberrant expression of farnesyl diphosphate synthase and SREBPs as well as prenyltransferases and their upstream regulators in an E2F-dependent manner. Consequently, isoprenylation is enhanced and N-Ras is activated; leading to elevated N-Ras activity, which induces DNA damage response and p130-dependent cellular senescence in RB-deficient cells (79). It is suggested that RBP targets many genes coding enzymes that participate in the biosynthesis of fatty acid and cholesterol. There are either sterol regulatory elements (SRE) or E2F‐binding consensus sequences or both in the promoter of these genes. Most implicated genes in the MVA pathway that governs farnesylation, geranylgeranylation, and cholesterol synthesis are trans-activated by SREBP. Since E2F and SREBP dually regulate SREBP genes, a different impact is made on genes involved in the MVA pathway by RBP (80,81). Collectively, studies have shown that SREBP-1 could be a potential candidate for treating glioma and its inhibitors (i.e., retinol and phytol) may help reach this goal (82–84).
ETC-1002 (Bempedoic acid) for the management of hyperlipidemia: from preclinical studies to phase 3 trials
Published in Expert Opinion on Pharmacotherapy, 2019
M. Ruscica, M. Banach, A. Sahebkar, A. Corsini, C. R. Sirtori
The selective inhibitory activity of bempedoic acid on ACLY is a mechanism whose therapeutic potential has been reported many years ago. (-)-Hydroxycitrate, a natural inhibitor of ACLY, was found to reduce cholesterol synthesis by 27% in HepG2 cells, with a concomitant rise in LDLR (+50%) activity and HMGCoA reductase (30-fold), an overall effect similar to that exerted by mevinolin [68]. Bempedoic acid, at doses between 120 and 180 mg/day, exerts a significant LDL-C reduction, with a significant fall of hsCRP. The excellent tolerability of bempedoic acid can be explained by the prodrug nature of this agent, which enables metabolic conversion to a CoA derivative, occurring only in the liver. Since ACSVL1 is not present in the skeletal muscle, inhibition of isoprenoid synthesis in muscle would not be expected, thereby potentially leading to less risk of myalgia symptoms and myopathy, that is of special value in the treatment of elderly patients [69]. It should be remembered that among potential mechanisms leading to statin-related myalgia [70], there is the lowered synthesis of non-steroidal isoprenoids [71]. Two of these, i.e. farnesyl pyrophosphate and geranylgeranyl pyrophosphate, are substrates of the prenyltransferase enzyme, involved in the post-translational modification of intracellular proteins, the so-called prenylation process [72]. The major roles of geranylgeraniol as well as of geranylfarnesol per se is the regulation of arterial myocyte proliferation induced by statins. Inhibition of cell growth induced by some statins (simvastatin or fluvastatin, but not pravastatin) [73] can be completely prevented by the addition of mevalonate, but partially (70–85%) by the addition of geraniol, farnesol, and geranylgeraniol [74]. Most recently, a detailed study on the mechanism of statin-associated myalgia, evaluating cellular stress, apoptosis and DNA senescence, reported activation of immunity and inflammation, and altered cellular signaling mediated by protein prenylation and RAS-GTPase activation in muscle [75]. Persistent myalgia in response to statins may, thus, come from cellular stress underpinned by post-inflammatory mechanisms of repair and regeneration. A subset of individuals may be genetically predisposed to an altered statin metabolism with increased susceptibility to a range of statin induce myopathies.