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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
Transcription factors are proteins that control the DNA transcriptional process by selectively binding to a target sequence in the promoter region of the relevant gene to stimulate or inhibit transcription. They work by modifying the activity of RNA Polymerase II (Pol II) to ensure that transcription occurs (or not) at the appropriate time and place in the genome. Cancer therapies based on inhibiting the transcription of oncogenes such as C-Myc, HIF-1, NFκB, and STAT-3 have been envisaged. A number of small molecules inhibitors have been reported such as alvocidib, echinomycin, PBD molecules (e.g., TSG-1301), and the hairpin polyamides that can bind to duplex DNA in a sequence-selective manner and inhibit transcription. Some of these molecules are described in Section 5.7.1.1.1, although none have reached the approval stage.
Mass Spectrometric Analysis
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
The quinoxaline group of antibiotics has been studied by FD and FAB methods. In a study of the chromophore’s role in intercalation of DNA by these antibiotics the quinoxaline groups were replaced with similar chromophores by direct synthesis with cultured media [265]. A total of eight analogs of echinomycin (Figure 3) were isolated and identified by FD. The molecular weights were obtained from either M+ or (M + H)+ and (M + Li)+ ions. In this way, the substitution of one quinoxaline by the new chromophore was distinguished from the substitution of both quinoxaline groups. The characterization of a triostin derivative in mycelial cultures supplemented with 6-methylquinoline- 2-carboxylic acid provided the first evidence that echinomycin is biosynthetically derived from triostin by S-methylation and subsequent rearrangement [266]. Using FAB, six analogs of triostin were also characterized [267]. The molecular weights were obtained from the (M - H)− ions in the negative ion mode. Efforts to obtain useful mass spectra were unsuccessful until a mixture of α-thioglycerol and glycerol was used for the matrix.
Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2016–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Hyun Seung Ban, Yoshikazu Uto, Hiroyuki Nakamura
The Children’s Research Institute, Children’s National Medical Center has deposited two applications regarding the use of echinomycin as an HIF inhibitor for graft versus host disease (GvHD), proliferative disease, leukemia, cancer, and autoimmune disease [40,41]. Echinomycin (compound 13 in Figure 2) is a quinoxaline antibiotic of bicyclic octapeptide isolated from Streptomyces echinatus [42,43]. Echinomycin (13) has a various biological activities including antibiotic and antitumor activity [44] Echinomycin (13) strongly binds to double-stranded DNA and inhibits RNA synthesis [45]. In addition, echinomycin (13) directly inhibits the binding of HIF-1α to the cis-element HRE, resulting in reduced expression of HIF-1 target genes [46]. In the application [40], the authors reported that HIF-1α accumulation was increased in the spleen of the GvHD mouse model, and disclosed that the use of the HIF-1 inhibitor echinomycin (13) to prevent the development of GvHD or reduce the severity of GvHD in a mammalian subject receiving an allogeneic hematopoietic stem cell (HSC) transplant. In another application [41], the authors disclosed a liposomal drug formulation of echinomycin for the treatment of a disease associated with overexpression of HIF-1α and/or HIF-2α. The authors reported the methods of preparation of liposomes encapsulating echinomycin (13) and a modification of PEGylated lipid to enhance the accumulation of liposomes in tumor tissue. In a human SUM159 breast cancer xenograft mouse model, administration of 0.35 mg/kg liposomal echinomycin (13) resulted in a 50% reduction in tumor growth. The investigators disclosed more details in a separate article [47].
HIF-α factors as potential therapeutic targets in leukemia
Published in Expert Opinion on Therapeutic Targets, 2018
Daniela Magliulo, Rosa Bernardi
In addition, echinomycin, an inhibitor of HIF-1α DNA binding with unknown effect on HIF-2α [48], reduced leukemia burden and leukemia repopulation by LSCs in mice transplanted with a human AML with no specific karyotypic aberration [71]. Echinomycin also slowed down tumor growth in AML1-ETO-driven AML, by acting on the AML1-ETO/HIF-1α/DNMT3A pro-oncogenic axis [69].