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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Both normal and mutated Ras proteins need to anchor to the cell membrane for signal transduction to occur (Figure 6.54). Attachment to the membrane occurs through several post-translational modifications, in particular the transfer of a 15-carbon isoprenoid group to the carboxy-terminal of the Ras protein, a process known as prenylation. This isoprenoid group ensures that Ras can attach to its correct intracellular membrane-bound location. Thus, the membrane-bound Ras protein represents a “molecular switch” that allows transport of a signal (e.g., a growth factor) from the external environment of a cell to its nucleus. The first stage of this process involves an extracellular ligand stimulating a monomeric receptor kinase (RTK) that then dimerizes. Next, Grb2, an initial adaptor protein, identifies and interacts with a binding site, which in turn allows recruitment of “Son of Sevenless” (SoS), a second adaptor protein. The latter causes the inactive GDP-carrying Ras to become active by substituting GDP for GTP. After this, the signal can be transmitted downstream by the activated Ras to other effectors, such as Raf. In the MAPK signaling pathway, the Raf protein is the first kinase in the signaling chain.
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
Synthetic isoprenoid analogues resulted in a great interest for studying protein prenylation, one of the most extensively studied post-translational modifications due to its crucial role in the regulation of diverse cellular processes. Compounds with a high affinity for the involved enzymes such as FPPS and GPPS have allowed active sites ad mechanisms of action to be characterized. Those analogues acting as inhibitors of isoprenoid biosynthesis are also important therapeutic drugs against a variety of important diseases including osteoporosis, Paget’s disease, metastatic diseases, cardiovascular disorders and even malaria. Some of those drugs are marketed and their utility has been widely demonstrated but they still present undesired side effects in many instances. Because of that, it is extremely important to have at disposition a battery of synthetic methodologies that allow introducing modifications in already known structures or, alternatively, creating new scaffolds that could serve as a next generation of inhibitors of isoprenoid biosynthesis of therapeutic utility.
Natural Polyketides to Prevent Cardiovascular Disease
Published in Catherina Caballero-George, Natural Products and Cardiovascular Health, 2018
Additionally, there are pleiotropic effects that the inhibition of the mevalonate pathway may incur as a result of this pathway’s role in the production of a number of key isoprenoid intermediaries. The effect is due to the role that prenylation, the addition of hydrophobic molecules to a protein, plays in protein trafficking and cellular signaling by facilitating protein-membrane interactions. First, farnesyl pyrophosphate signals protein transport to the lumen of the endoplasmic reticulum for further modification and is implicated in interactions involving Ras family proteins. Second, geranylgeranyl pyrophosphate plays a role in the modulation of the RhoA, Rac and Cdc signaling pathways. These are integral GTPase proteins for cellular growth, proliferation and migration that are employed ubiquitously across normal cell types and are often the subject of mutation in tumorigenic cells (Liao and Laufs, 2005).
Progeria: a perspective on potential drug targets and treatment strategies
Published in Expert Opinion on Therapeutic Targets, 2022
Ignacio Benedicto, Xue Chen, Martin O Bergo, Vicente Andrés
Additional strategies to treat progeria were based on the idea that progerin and prelamin A, like K-RAS, might undergo alternative prenylation by protein geranylgeranyltransferase type I (GGTase-I) when FTase is inhibited by FTIs [4]. In line with this idea, bone density was partially preserved, and survival increased in progeroid Zmpste24–/– mice upon treatment with statins and aminobisphosphonates, which inhibit both the farnesylation and the geranylgeranylation of progerin/prelamin A [28]. However, the results of a single-arm triple therapy trial revealed no additional benefit of combining lonafarnib with pravastatin and zoledronate compared with lonafarnib monotherapy [29]. The idea that statins and bisphosphonates inhibit prenylation is based on the exposure of cultured cells to high drug doses, which reduce and even block prenylation of certain substrates in this setting. However, there is little or no robust evidence that these classes of drugs inhibit either farnesylation or geranylgeranylation in human tissues in vivo. It is also possible that progerin contributes to HGPS pathogenesis due in part to the lack of 50 amino acids in its C-terminus compared to normal lamin A, an alteration that is not expected to be corrected by FTIs and geranylgeranylation inhibitors.
Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design
Published in Expert Opinion on Drug Discovery, 2022
Kashif Haider, Anku Sharma, M Shahar Yar, Prasanna Anjaneyulu Yakkala, Syed Shafi, Ahmed Kamal
In human cells, major RAS oncogenes include KRAS, NRAS, and HRAS encode for KRAS (4A and 4B), HRAS, and NRAS, respectively. In RAS protein, the catalytic site has much higher similarity among all isoforms, which contains P-loop, switches I and II and RAS-effector interaction interfaces. RAS GTPases contain a CAAX motif, which serves as the substrate for a series of post-translational modifications. These modifications include initial prenylation by the covalent attachment of farnesyl pyrophosphate or geranyl pyrophosphate at the CAAX box (termed as farnesylation and geranylation, respectively), whereas HRAS can be only farnesylated. Most of the RAS proteins can be farnesylated and as well as geranylated. After prenylation, three-terminal amino acid residues (AAX) are removed at the endoplasmic reticulum. The carboxy group of terminal cysteine is methylated by an enzyme called isoprenylcysteine carboxymethyltransferase (ICMT). Except for KRAS4B, other RAS proteins then undergo palmitoylation at the adjacent cysteine residue and are transported to the plasma membrane by active vesicular transport [3]. Finally, the inner membrane of RAS activation is controlled through positive guanine nucleotide exchange factors (GEFs) and negative GTPase activating proteins (GAPs) (Figure 1) [4].
Progress in the development of novel therapies for choroideremia
Published in Expert Review of Ophthalmology, 2019
Jasmina Cehajic Kapetanovic, Maria I Patrício, Robert E MacLaren
The levels of REP1 in peripheral blood mononuclear cells can be measured in vitro by immunoblot assays. The absence or reduced levels of REP1 can be used to support the diagnosis of choroideremia. Moreover, the detection of reduced prenylation activity can further aid the diagnosis. These premises led to the investigation of a method to test the biological activity of AAV vector carrying CHM gene currently under trial for choroideremia. We recently developed a robust in vitro prenylation assay using a biotinylated lipid donor to test the REP1 activity following the transduction of HEK293 cells with AAV2-REP1 [17]. Specifically, two Rab proteins, RAB27A and RAB6A, were used as substrates in a prenylation reaction in which a biotinylated lipid donor was incorporated. The amount of biotinylated lipid donor detected was proportional to the amount of AAV2-REP1 present in the reaction. We also found that the prenylation of RAB6A is more sensitive to REP1 protein expression compared to RAB27A. This method was found to be robust and reproducible in several cell lines. This assay can be used to test the biological activity of AAV vectors in choroideremia gene therapy clinical trials.