Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Namrita Lall in Medicinal Plants for Cosmetics, Health and Diseases, 2022
Cyclic peptides, also referred as ‘macrocyclic’ compounds, inhibit HDAC by interacting with the outer rim of the enzyme (Mwakwari et al., 2010). These cyclic compounds usually contain complex cap-groups which bind to the HDAC’s outer rim regions, thereby inhibiting the enzyme activity with more potency and isoform selectivity (Maolanon et al., 2016). Based on their macrocyclic moieties, these HDACi are subdivided into: (a) cyclic peptides; and (b) depsipeptides. The first class contains a mixture of L- and D-amino acids and cyclic amino acids such as proline or pipecolic acid (Mwakwari et al., 2010). Examples of cyclic peptides are trapoxin-A and trapoxin-B, apicidin (a fungal metabolite from fusarium species), azumamide (isolated from Mycale izuensis) and HC-toxin (Mwakwari et al., 2010).
General concepts for applied exercise physiology
Nick Draper, Helen Marshall in Exercise Physiology, 2014
The concept behind periodisation is to divide the training year into distinct phases. These phases build upon one another to prepare an athlete for a specific event or season of competition. Programmes can be designed over a short or long period of time and developed individually for an athlete. The possible phases within a periodised programme are shown in Table 8.3. The most common length of time for a periodised programme would be a one-year plan; this is dependent on the level of performance and age of the athlete(s). The phases in a periodised programme have specific names. A macrocycle is the largest unit of a programme such as a training year. Macrocycles are subdivided into a number of mesocycles which last for one to several months. Mesocycles are comprised of a number of microcycles which are typically one week long. By structuring a programme in this way, it is possible for an athlete to put the next training session in context with the whole week’s training, and to visualise how that week links to the next mesocycle and how the full programme leads to the event for which they are training.
Radioimmunotherapy of Ovarian Cancer
David M. Goldenberg in Cancer Therapy with Radiolabeled Antibodies, 1995
The chelating macrocycle DOTA had very promising in vitro properties,96 however it had significant immunogenicity97 and clinical side effects in 50% of patients treated.98 A phase I toxicity study assessing CITC-DTPA, another chelating agent, has recently been completed." It emerged that this molecule, despite not being a macrocycle, is also serologically immunogenic (Kosmas et al., manuscript in preparation) in a significant proportion of patients. Clinically important but self-limiting side-effects were observed in 5 of the 19 patients treated." An estimated amount of 18.5 to 19 mCi/m2 was administered which represents an at-least twofold increase of amount of radioactivity as compared to the DTPA conjugate. A relation between radiation dose per square meter of body surface area and bone marrow toxicity was observed (Figure 2). Bone marrow toxicity was easily manageable on an outpatient basis (Figure 3). Vriesendorp et al.100 have administered 50 to 80 mCi intravenously in patients with lymphoma together with bone marrow rescue. The next toxicity if the bone marrow is spared seems to be radiation hepatitis at least in beagle dogs.101
Anaplastic lymphoma kinase inhibitors: an updated patent review (2014–2018)
Published in Expert Opinion on Therapeutic Patents, 2020
Yi-Min Liu, Chun-Nan Kuo, Jing-Ping Liou
However, a newly encountered difficulty after the introduction of crizotinib was the development of resistance. Therefore, new ALK inhibitors that can overcome the resistance were developed. Through structural modification of different generations and/or underdevelopment of ALK inhibitors, the macrocyclic compounds have been emerged, such as lorlatinib and repotrectinib. Recently, several references have also mentioned about the macrocyclic compounds may provide a new vision to enhance potency, selectivity, stability, and the ability to against resistance. Boehringer Ingelheim Pharmaceuticals reported the rigidification concept of EGFR tyrosine kinase inhibitors. They rigidified the original compound through macrocyclization to generate compound BI-4020 as an EGFR inhibitor. BI-4020 is a noncovalent, macrocyclic TKI, which inhibits not only the triple mutant EGFRdel19 T790M C797S variant but also the double mutant EGFRdel19 T790M and primary mutant EGFRdel19 while sparing activity against EGFRwt. BI-4020 also shows high potency on EGFR mutant cells, high kinome selectivity, and good DMPK properties, which led to tumor regression in the human PC-9 (EGFRdel19 T790M C797S) triple mutant NSCLC xenograft model in mice [98].
A patent review on PD-1/PD-L1 antagonists: small molecules, peptides, and macrocycles (2015-2018)
Published in Expert Opinion on Therapeutic Patents, 2018
Shabnam Shaabani, Harmen P.S. Huizinga, Roberto Butera, Ariana Kouchi, Katarzyna Guzik, Katarzyna Magiera-Mularz, Tad A. Holak, Alexander Dömling
Bristol-Myers Squibb described also macrocyclic peptides with general structures 34 [41–45] and 35 [46] which were characterized by nanomolar and submicromolar activities in the HTRF binding assay. The most potent examples of these inhibitors of PD-1/PD-L1 and PD-L1/CD80 interactions with IC50 values in the range of 2.5 nM–8 nM are shown in Scheme 14. All of these compounds consist of sulfide bonds and indole ring in their structure. Among all of the macrocyclic compounds reported by BMS company, example 68 has the lowest IC50 value of 2.5 nM in HTRF human PD-L1/PD-1 binding assay. An interesting class of macrocyclic compounds with general structure 34 claimed as inhibitors of PD-1/PD-L1 and PD-L1/CD80 PPIs are bicyclic macrocycles. Example 72 as a representative of the bicyclic macrocycles with the lowest HTRF IC50 value reported for this class of macrocycles is shown in Scheme 14 [45].
Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Recently, macrocyclic compounds have received great attention in drug discovery due to their unique physicochemical properties as well as high potential to offer broader intellectual property (IP) [72–75]. In addition, with cyclization, the structural conformation will be pre-organized, which could result in high affinity and selectivity for protein targets. Several macrocyclic kinase inhibitors have been progressed into market or clinical trials with good potency and selectivity for their targets [76–78]. Ipsen Pharma in collaboration with Oncodesign was the first organization to incorporate the macrocycle strategy to LRRK2 inhibitors with three patents (WO2013046029, WO2014140235 and WO2016042089) filed which further expanded the LRRK2 small molecule landscape [79–81]. The general structures 50, 51 and 52 (Figure 12) for the three applications were published with macrocyclic pyrazolopyrimidines or imidazopyridazines as the novel scaffolds, and most of the derivatives demonstrated potent LRRK2 enzymatic activities (IC50 < 100 nM). The first two applications explored acyclic linkers derived from 3,5-disubstituted cores containing 77 and 57 compounds, respectively. The application filed in 2013 focused on amide or sulfonyl substituted linkers as illustrated by compound 52, and the one filed in 2014 focused on the secondary amine or ether linker as illustrated by compound 54. Their third application in 2016 then further expanded the linker to heterocyclic aliphatic groups including mono- or fused-bicyclic rings as exemplified by compound 55.
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