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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
Protein prenylation, in particular farnesylation and geranylgeranylation, is one of the essential post-translational protein modifications in the eukaryote in which protein prenyltransferases catalyze the transfer of FPP or GGPP to cysteine residues located in conserved prenylation target motifs at the C-terminus of the protein substrate (Clarke, 1992; Merino et al., 2017). This post-translational modification is required for the proper membrane localization and biological function of numerous proteins (Hancock et al., 1989; Kitten and Nigg, 1991; Zhang and Casey, 1996).
The YPT Protein Family in Yeast
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
Warren A. Kibbe, Ludger Hengst, Dieter Gallwitz
The C-termini of members of the ras superfamily contain a critical cysteine residue necessary for membrane attachment. In the case of Ras proteins, the C-terminal sequence is the conserved motif CAAX, where C is cysteine, A is any aliphatic amino acid, and X is any amino acid. The modification of the CAAX motif during maturation is necessary for the proper attachment of Ras proteins to the plasma membrane, but is not in itself sufficient for membrane association.72 In mammalian cells as well as in the yeast S. cerevisiae, the C-terminal cysteine residue is modified by covalent linkage with a farnesyl moiety.73-75 Farnesylation is catalyzed by a transferase composed of two nonidentical subunits.76,77
Specific Therapy for Leukemias
Published in Tariq I Mughal, John M Goldman, Sabena T Mughal, Understanding Leukemias, Lymphomas, and Myelomas, 2017
Tariq I Mughal, John M Goldman, Sabena T Mughal
Other potentially useful tyrosine kinase inhibitors in clinical studies include the FLT-3 and KIT inhibitors, such as the drug SU11248 which is directed against the high levels of these receptors found in AML. A related drug, tipifarnib (Zarnestra; R115777), which inhibits an enzyme (farnesyl-transferase) involved in protein processing (farnesylation), is also in clinical studies, with encouraging interim results. This drug, by preventing the activation of RAS oncogenes, is able to inhibit cell growth and angiogenesis and induce apoptosis.
Lessons learned from the discovery and development of the sesquiterpene lactones in cancer therapy and prevention
Published in Expert Opinion on Drug Discovery, 2022
Israa A. Cheikh, Chirine El-Baba, Ali Youssef, Najat A. Saliba, Akram Ghantous, Nadine Darwiche
Arglabin is used alone or in combination with other therapies to treat liver, ovarian, uterine cervix, lungs, and breast cancers in Kazakhstan, USA, Germany, Russia, Georgia Kirghiz Republic, Uzbekistan, and Belarus [217]. Interfering with RAS-oncogenes farnesylation is considered an attractive strategy for anticancer drug development [81]. Interestingly, the administration of 370 mg/m2 of arglabin every first week of a 21-day cycle decreased H-Ras oncoproteins in breast cancer patients. Patients treated with arglabin combined with doxorubicin and cyclophosphamide chemotherapy regimen (CN-02296454) showed variable reduction in the levels of H-Ras oncoproteins [218]. Arglabin monotherapy was more promising then combination treatments as also noted in advanced breast cancer patients (CN-01430638) [219]. Therefore, the addition of arglabin to cyclophosphamide‐protocol in anticancer therapeutic regimens does not improve tumor response rates. However, it increases the three‐year disease‐free survival rate by 28% compared to the standard cyclophosphamide regimen (CN-01664526) [220].
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].
Novel insights into the pathogenesis and treatment of NRAS mutant melanoma
Published in Expert Review of Precision Medicine and Drug Development, 2021
Jeffrey Zhao, Carlos Galvez, Kathryn Eby Beckermann, Douglas B. Johnson, Jeffrey A Sosman
Alterations in post-translational modification in addition to acquired secondary mutations may frequently drive drug resistance in melanoma. Post-transcriptional and post-translational changes may be playing a role. Farnesylation and palmitoylation have been explored as possible targets of novel therapies. NRAS plasma membrane localization is dependent on a cycle of palmitoylation and depalmitolyation mediated by the enzymes acyl protein thioesterases 1 and 2 (APT-1, APT2), respectively [110–112]. Palmostatin B inhibits NRASG12D hematopoietic cells in vitro through a mechanism that disrupts physiologic NRAS membrane localization. RAS family GEF and GAPs are also being explored in preclinical studies, though there have been no breakthroughs with targeting these GTPase enzyme mediators for NRAS melanoma [113]. Post-translational protein modification pathways including ubiquitin-mediated degradation offer another avenue of attack. The E3 ubiquitin ligase encoded by MDM2 is selectively inhibited by the small molecule, PDX1826, which in combination with CDK4/6i therapy resulted in decreased melanoma growth in vivo and in patient-derived xenografts [114].