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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
RNA folding follows a hierarchical pathway analogous to that observed for proteins. The primary base sequence dictates the type of secondary structure formed, which in turn allows the formation of a possible tertiary structure via interaction of preformed secondary structures. Formation of RNA secondary structure dominates the free energy of folding, as each base pair contributes 1–3 kcal/mol of free energy to the final fold. For example, transfer RNAs (tRNAs) have a uniquely evolved tertiary structure, and their primary sequence directs a “clover leaf” secondary structure composed of three stem-loop segments. However, the well-known three-dimensional structure of tRNAs is finalized by the interaction between two of the hairpin loops (the T- and C-loops). This last step, the formation of tertiary structure, contributes only 1.5 kcal/mol of free energy. With regard to small molecule targeting, the secondary structure is generally regarded as the key determinant in defining the “druggability” of a particular RNA.
Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
To address the failure rate between ligand and drug, many computational approaches have been developed for the optimization of druggability, blood-brain barrier penetration, lipophilicity, and metabolism. All the computational approaches contribute to more cost-effective discovery and optimization of compounds, accelerating progress toward the clinic. Such high-throughput methods with the power to consider multiple targets at the same time are particularly effective and useful for designing multi-target drugs as will be considered in the next section.
Novel Anti-Cancer Drugs Based On Hsp90 Inhibitory Mechanisms: A Recent Report
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
The druggability of Hsp90 was first established in 1994 with the help of the natural product, geldanamycin (GA) [57]. Geldanamycin is a benzoquinone anamycin isolated from Streptomyces hygroscopicus. It was experimentally shown that GA competitively blocks the N-terminal ATP binding pocket of Hsp90, which leads to ubiqitin mediated proteosomal degradation of the client proteins [58, 59]. However, this drug molecule failed to reach clinical trials because of poor aqueous solubility, in vivo unstability and severe hepatotoxicity (attributed to its quinone moiety) [60]. This paved the pathway for the development of various effective geldanamycin derivatives [17-allyl amino–17-demethoxy-geldanamycin (17-AAG, Tanespimycin), 17-desmethoxy–17-N, N-dimethylaminoethyl amino geldanamycin (17-DMAG, Alvespimycin), reduced hydroquinone form of 17-AAG (Retaspimycin or IPI–504). 17 AG (17-amino–17-desmethoxygeldanamycin, IPI–493)] with improved solubility, toxicological properties and aqueous solubility (Figure 3.5) [61]. 17-AAG was the first geldanamyicn derivative to reach clinical trials alone (phase-I/II) [62, 63] and in combination with trastuzumab (phase-I) [64]. However, this chemical entity was discontinued due to poor pharmaceutical properties and patent-related concerns [65]. The water-soluble geldanamycin derivative, alvespimycin reached phase I clinical studies owing to its better safety and formulation profile [66–68]. However, the development of this Hsp90 inhibitor was halted due to huge investment required for its further clinical studies and subsequent commercialization [69]. The other oral GA analog that reached phase II/III clinical trials are retaspimycin or IPI–504 [70–72]. This chemical entity demonstrated high mortality rate among subjects and was hence not developed further [73]. IPI–493 another Hsp90 antagonist that reached phase-I clinical studies [74, 75]. This analog of GA was not taken up for advanced studies because of formulation issues and dose administration difficulties [76]. Several other potent natural GA analogs were discovered by genetic engineering techniques and mutasynthesis [77] (like macbecin, Figure 3.5). Despite showing excellent in vitroefficacy, these agents were found to be ineffective for testing in human subjects [76, 78].
Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper
Published in mAbs, 2022
Karelle Ménochet, Hongbin Yu, Bonnie Wang, Jay Tibbitts, Cheng-Pang Hsu, Amrita V. Kamath, Wolfgang F. Richter, Andreas Baumann
During drug development, it is often necessary to determine whether a target is “druggable”. The druggability of a target can be related to a number of characteristics, including tissue distribution or location, and expression and turnover. Drug targets with high levels of expression and/or turnover, particularly in non-target tissues can pose challenges due to the high amounts of drug required to sustain sufficient levels of occupancy to drive the desired pharmacologic effects. An excellent example of this is CCL21, a soluble chemokine believed to play a role in modulating inflammation. QBP359 is a human IgG1 mAb that binds specifically to human CCL21 and cross-reacts with cynomolgus monkey, but not with mouse CCL21.60, 61 The similarity in binding of QBP359 between NHP and humans, and the physiologic similarities between these species, made the NHP a suitable system to explore the PKPD of this novel biotherapeutic for the purposes of estimating human efficacious dose. In a dose-range finding NHP toxicology study, the elimination rate of QBP359 was found to be rapid compared to a typical IgG and decreased as the dose increased, suggesting that CCL21 occupancy was not achieved at the low dose used in that study (10 mg/kg weekly). This raised questions about the ability of QBP359 to sufficiently suppress CCL21 concentrations at manageable doses. Subsequent PK and biodistribution studies in the NHP were conducted to enable a more complete assessment of the PK of QBP359 and the dynamics of CCL21 turnover, and information on the tissue localization of CCL21.
Preclinical target validation for non-addictive therapeutics development for pain
Published in Expert Opinion on Therapeutic Targets, 2022
Richard Hargreaves, Karen Akinsanya, Seena K. Ajit, Neel T. Dhruv, Jamie Driscoll, Peter Farina, Narender Gavva, Marie Gill, Andrea Houghton, Smriti Iyengar, Carrie Jones, Annemieke Kavelaars, Ajamete Kaykas, Walter J. Koroshetz, Pascal Laeng, Jennifer M. Laird, Donald C. Lo, Johan Luthman, Gordon Munro, Michael L. Oshinsky, G. Sitta Sittampalam, Sarah A. Woller, Amir P. Tamiz
In research programs that are based on targets selected from human pain disorders, it is important to test mechanistic hypotheses that align targets with outcomes in specific populations of pain patients at the outset even if other mechanisms may be at work. In an ideal scenario, this hypothesis would draw a detailed connection between the proposed target and the diagnostic indication through characterization of molecular mechanisms, cellular and circuit-level mechanisms, disease pathophysiology, patient phenotypes, and relevant outcome measures [16]. A final consideration is the target’s ‘druggability’ – that is, can an efficacious, safe, and cost-effective therapy be developed? The number of published human pain studies from which to gather these supporting data is increasing. However, the extent of human evidence supporting a particular target may range from nonexistent, with only preclinical associations, to comprehensive validation, such as that found when a drug is already on the market.
A Novel Compound Plumercine from Plumeria alba Exhibits Promising Anti-Leukemic Efficacies against B Cell Acute Lymphoblastic Leukemia
Published in Nutrition and Cancer, 2022
Aaheli Chatterjee, Amrita Pal, Santanu Paul
The success of Drug development or drug designing is highly conditioned by the characteristics of the targets used (44). It is generally predicted by its affinity to interact with drugs that are supposed to provide some therapeutic benefits (45). Druggability can also be predicted based on the properties of ligand or the drug binding and is known to be ligand based druggability. This is mainly done for biotherapeutic reagents (46) Druggability properties include factors like Lipinski’s rule of five violations, Solubility Forecast Index, QEDw score etc. According to Lipinski’s rule of five violations for an orally active drug there should not be more than one violation of the five rules. As observed in Table 3, Plumericine and Isoplumercine have shown 0 violation to Lipinski’s rule of five violations which brings out the fact about their good druggability. On the other hand 13-O-p-Coumaroylplumieride has shown two violations which are considered to be a negative aspect toward drug development. Similar type of results is shown by Veber Rule and Egan rule which predicts the oral bioavailability of the compounds. Plumericine and Isoplumericine have shown good results compared to 13-O-p-Coumaroylplumieride. Though all of the given compounds show good solubility index, the chances to become potential drug candidate is observed more in case of Plumericine and Isoplumercine depending on their druggability properties. Different druggability properties of Plumercine, Isoplumericine and 13-O-p-Coumaroylplumieride are listed in Table 3.