生物活性

• 描述Histone deacetylases (HDACs) are epigenetic regulators that regulate the histone tail, chromatin conformation, protein-DNA interaction, and even transcription. HDACs are also post-transcriptional modifiers that regulate the protein acetylation implicated in several pathophysiologic states^[2]. In 200 breast cancer samples, HDAC1 and 3 expression was found to correlate with oestrogen and progesterone receptor expression and HDAC-1 expression predicted better disease free survival. Multivariate analysis demonstrated that HDAC-1 was an independent prognostic marker^[3]. In acute promyelocytic leukemia cells, HDAC3 is a key component of the aberrant transcription regulation in PML-RARa-expressing cells. Knockdown of HDAC3 in these cells restores expression of retinoic acid dependent genes^[4]. HDAC inhibitors can provide a therapeutic effect in various cancers, such as B-cell lymphoma, leukemia, multiple myeloma and some virus-associated cancers. Some evidence has demonstrated that HDAC inhibitors can increase the expression of immune-related molecules leading to accumulation of CD8+ T cells and causing unresponsive tumor cells to be recognized by the immune system, reducing tumor immunity^[5]. NKL 22 (compound 4b) is a potent and selective inhibitor of HDAC, with an IC50 of 199 and 69 nM for HDAC1 and HDAC3, respectively^[6]. NKL 22 exhibits selectivity over HDAC2/4/5/7/8 (IC50≥1.59 μM)^[7]. NKL 22 ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice^[8].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02799472	Arthritis, Rheumatoid	Phase 2	Completed	-	United States, California ... more >> GSK Investigational Site El Cajon, California, United States, 92020 United States, Florida GSK Investigational Site Fort Lauderdale, Florida, United States, 33309 GSK Investigational Site Miami, Florida, United States, 33015 GSK Investigational Site Pinellas Park, Florida, United States, 33781 United States, Illinois GSK Investigational Site Chicago, Illinois, United States, 60616 United States, Pennsylvania GSK Investigational Site Duncansville, Pennsylvania, United States, 16635 United States, Tennessee GSK Investigational Site Memphis, Tennessee, United States, 38119 United States, Texas GSK Investigational Site Houston, Texas, United States, 77024 Germany GSK Investigational Site Freiburg, Baden-Wuerttemberg, Germany, 79106 GSK Investigational Site Erfurt, Thueringen, Germany, 99096 GSK Investigational Site Puettlingen, Germany, 66346 Poland GSK Investigational Site Elblag, Poland, 82-300 GSK Investigational Site Nowa Sol, Poland, 67-100 GSK Investigational Site Piaseczno, Poland, 05-500 GSK Investigational Site Warszawa, Poland, 00-660 GSK Investigational Site Warszawa, Poland, 03-291 GSK Investigational Site Wroclaw, Poland, 51-128 Collapse <<
  NCT02799472	-	-	Completed	-	-

• 参考文献

• [1] Herman D, Jenssen K, et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. Nat Chem Biol. 2006 Oct;2(10):551-8. Epub 2006 Aug 20. Erratum in: Nat Chem Biol. 2007 Jul;3(7):432.

  [2] Somy Yoon,et al. HDAC and HDAC Inhibitor: From Cancer to Cardiovascular Diseases. Chonnam Med J. 2016 Jan;52(1):1-11.

  [3] C.A. Krusche, et al. Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysis, Breast Cancer Res. Treat. 90 (2005) 15–23.

  [4] A. Atsumi, et al, Histone deacetylase 3(HDAC3) is recruited to target promoters by PML-RARa as a component of the N-CoR co-repressor complex to repress transcription in vivo, Biochem. Biophys. Res. Commun. 345 (2006)1471–1480.

  [5] I-Chung Chen,et al. Recent Update of HDAC Inhibitors in Lymphoma. Front Cell Dev Biol. 2020 Sep 3;8:576391.

  [6] Jia H, et, al. Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease. Neurobiol Dis. 2012 May;46(2):351-61.

  [7] D Herman et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. Nat Chem Biol, 2006 Oct, 2(10):551-8.

  [8] Thomas EA, et, al. The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15564-9.

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