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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
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).
How to manage lymphatic leakage involved in lymphangioma?
Published in Byung-Boong Lee, Peter Gloviczki, Francine Blei, Jovan N. Markovic, Vascular Malformations, 2019
Xi Yang, Xiaoxi Lin, Ningfei Liu
Sirolimus, also known as rapamycin, is a macrocyclic compound that exhibits potent immunosuppressive effects and is used in organ transplants to prevent rejection reactions. It inhibits the signaling pathway mammalian target of rapamycin (mTOR) involved in important cellular functions including cellular proliferation and angiogenesis.21 As the abnormal mTOR activity is associated with hamartomatous tumors and vascular proliferations, sirolimus has been used in lymphatic malformations. Both oral and topical sirolimus proved to be effective in the treatment of LC. Rössler et al. reported two cases where oral sirolimus was highly effective in alleviating lymph leakage and other symptoms.14 Çalışkan and García-Montero reported one and two cases, respectively, of LC treated by topical sirolimus that also showed significant improvement and no side effects.19, 22 Oral sirolimus treatment is associated with side effects including headache, oral ulcers, neutropenia, gastrointestinal problems, and elevations in liver function tests and serum lipids. The side effects of topical sirolimus are much less. The most common side effects of topical sirolimus have been reported as irritation and a burning sensation at the site of application. However, as the penetration capacity of topical sirolimus is weak, probably the deeper lesions will not benefit from the therapy. Additionally, the recurrence of lesions after the discontinuation of the drug suggests that long-term use is mandatory for control of the disease.
Biologic Drug Substance and Drug Product Manufacture
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Ajit S. Narang, Mary E. Krause, Shelly Pizarro, Joon Chong Yee
These drugs are exemplified by peptides, such as cyclosporin, and macrocyclic compounds, such as amphotericin B (Giordanetto and Kihlberg 2014). These compounds are typically synthetic or semi-synthetic in origin and are prepared as parenteral formulations, due to their low oral bioavailability. Considerations in the parenteral formulation of these compounds are fairly similar to those of small molecule and large molecule parenteral drugs, including factors such as pH, ionic strength, osmotic pressure, drug and salt concentration, pyrogenicity, and sterility.
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].
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.
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].