生物活性

• 靶点	HDAC6 IC50:40nM-140nM

• 描述HDACs are a group of enzymes that remove acetyl groups and regulate the histone tail, protein-DNA interaction, chromatin conformation, and even transcription. There are 18 mammalian HDACs divided into four classes: class I (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10), class III (sirtuin family: sirt1-sirt7) and class IV (HDAC 11)^[1]. Pracinostat (SB-939) is identified as a potent hydroxamate-based inhibitor of class I, II and IV HDACs, inhibiting the isolated enzymes with IC50 values of 43 to 140 nM, 40 to 137 nM (class II), and 93 nM (class IV) with the exception of HDAC6. Pracinostat is effective on cell proliferation of various kinds of human cancer cell lines, including T-cell lymphoma cells and leukemia cells with IC50 values ranging from 50 nM to 170 nM, colon and prostate cancer cell lines with IC50 values ranging from 340 to 540 nM. However, no inhibition of the proliferation of normal human dermal fibroblasts at concentrations up to 100 μM can be observed. Treatment of pracinostat >0.125 μM can induce ac-H3 and the acetylation of α-tubulin in HCT-116 cells after 24h. Meanwhile, pracinostat >0.25 μM leads to decreased retinoblastoma serine phosphorylation on S807/811 and an increase of the cyclin-dependant kinase inhibitor p21Cip/WAF. Echoed to that, the increase in cell cycle arrest goes hand in hand with a dose-dependent increase of PARP. In animal study, a single dose of either 50 or 125 mg/kg of pracinostat causes increased ac-H3 in the tumor tissue of HCT-116 xenografted nude mice. Oral treatment of pracinostat once a day for 21 days, on dose of 100 mg/kg, achieves 94% tumor growth inhibition. These results show the superior pharmacokinetic and pharmacodynamic properties of pracinostat in in vivo study^[2]. A phase 3 study of pracinostat in combination with azacitidine in adults with acute myeloid leukemia and a phase 2 study of pracinostat with azacitidine in patients with previously untreated myelodysplastic syndrome can be seen (https://www.cancer.gov/).
• 作用机制Pracinostat is an hydroxamate-based HDAC inhibitor, structure of which can chelate Zn ion of HDACs.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  HCT116 cells	-	Proliferation assay	48 h	Antiproliferative activity against human HCT116 cells after 48 hrs by sulforhodamine B assay, GI50=0.24 μM	24119555
  MCF7 cells	-	Proliferation assay	48 h	Antiproliferative activity against human MCF7 cells after 48 hrs by sulforhodamine B assay, GI50=0.17 μM	24119555
  MDA-MB-435 cells	-	Proliferation assay	48 h	Antiproliferative activity against human MDA-MB-435 cells after 48 hrs by sulforhodamine B assay, GI50=0.48 μM	24119555

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• 动物研究
  剂量	Mice[4] (p.o.): min = 50 mg/kg, max = 200 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Nude mice[2] Administration i.d. Cmax 2632 ng/ml T1/2 2.44 h AUC0→∞ 1841 ng·h/L F 0.34 Tmax 0.17 h AUC0→last 1836 ng·h/L

• 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
  NCT00504296	Unspecified Adult Solid Tumor,... more >> Protocol Specific Collapse <<	Phase 1	Completed	-	Canada, Ontario ... more >> Juravinski Cancer Centre at Hamilton Health Sciences Hamilton, Ontario, Canada, L8V 5C2 Univ. Health Network-Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 Collapse <<
  NCT01184274	Leukemia Soli... more >>d Tumours Collapse <<	Phase 1	Completed	-	Canada, Alberta ... more >> Alberta Children's Hospital Calgary, Alberta, Canada, T3B 6A8 Stollery Children's Hospital Edmonton, Alberta, Canada, T6G 2B7 Canada, British Columbia Children's and Women's Health Centre of BC Branch Vancouver, British Columbia, Canada, V6H 3V4 Canada, Manitoba CancerCare Manitoba Winnipeg, Manitoba, Canada, R3E 0V9 Canada, Nova Scotia Izaak Walton Killam (IWK) Health Centre Halifax, Nova Scotia, Canada, B3K 6R8 Canada, Ontario Children's Hospital of Eastern Ontario Ottawa, Ontario, Canada, K1H 8L1 Hospital for Sick Children Toronto, Ontario, Canada, M5G 1X8 Canada, Quebec CHU Sainte-Justine Montreal, Quebec, Canada, H3T 1C5 Collapse <<
  NCT01200498	Myeloproliferative Disorders	Phase 2	Completed	-	United States, Texas ... more >> UT MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<

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• 参考文献

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

  [2] Novotny-Diermayr V, Sangthongpitag K, et al. SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer. Mol Cancer Ther. 2010 Mar;9(3):642-52.

  [3] Mottamal M, Zheng S, et al. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules. 2015 Mar 2;20(3):3898-941.

  [4] Wang H, Yu N, et al. Discovery of (2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an orally active histone deacetylase inhibitor with a superior preclinical profile. J Med Chem. 2011 Jul 14;54(13):4694-720.