Pyridostatin (trifluoroacetate salt) is a highly selective G-quadruplex-binding small molecule that was designed to target polymorphic G-quadruplex structures regardless of sequence variability. As a highly selective G-quadruplex DNA stabilizer,Kd is 490 nM. Pyridostatin has anti-proliferative effects and induces telomere dysfunction[1-4].
Pyridostatin(2 µM pyridostatin;24 h) induced DNA damage and checkpoint-dependent cell-cycle arrest in MRC-5 SV40 cells[5]. Pyridostatin(0.01-5 µM pyridostatin;24-96 h) induced neurotoxicity and promoted the formation of DNA double-strand breaks (DSBs) in cultured neurons[6]. Pyridostatin(10 µM pyridostatin;24 h) significantly downregulated 22 proteins but upregulated 16 proteins in HeLa cancer cells, of which the genes both contain a number of G4 potential sequences, Pyridostatin regulation on gene expression is far more complicated than inducing/stabilizing G4 structures[7].
References:
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[2]. Patel DJ, Phan AT, et,al. Human telomere, oncogenic promoter and 5'-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics. Nucleic Acids Res. 2007;35(22):7429-55. doi: 10.1093/nar/gkm711. Epub 2007 Oct 2. PMID: 17913750; PMCID: PMC2190718.
[3]. MÜller S, Kumari S, et,al. Small-molecule-mediated G-quadruplex isolation from human cells. Nat Chem. 2010 Dec;2(12):1095-8. doi: 10.1038/nchem.842. Epub 2010 Oct 10. PMID: 21107376; PMCID: PMC3119466.
[4]. Koirala D, Dhakal S, et,al. A single-molecule platform for investigation of interactions between G-quadruplexes and small-molecule ligands. Nat Chem. 2011 Aug 28;3(10):782-7. doi: 10.1038/nchem.1126. PMID: 21941250; PMCID: PMC3277938.
[5]. Rodriguez R, Miller KM, et,al. Small-molecule-induced DNA damage identifies alternative DNA structures in human genes. Nat Chem Biol. 2012 Feb 5;8(3):301-10. doi: 10.1038/nchembio.780. PMID: 22306580; PMCID: PMC3433707.
[6]. Moruno-Manchon JF, et,al. The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons. Aging (Albany NY). 2017 Sep 12;9(9):1957-1970. doi: 10.18632/aging.101282. PMID: 28904242; PMCID: PMC5636668.
[7]. Hou Y, Gan T, et,al. G-quadruplex inducer/stabilizer pyridostatin targets SUB1 to promote cytotoxicity of a transplatinum complex. Nucleic Acids Res. 2022 Apr 8;50(6):3070-3082. doi: 10.1093/nar/gkac151. PMID: 35258624; PMCID: PMC8989551.