生物活性

• 靶点	HDAC IC50:5nM

• 描述HDACs (Histone deacetylases) 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]. Panobinostat, also called as LBH-589 or NVP-LBH589, is broad-spectrum HDAC inhibitor with hydroxamate-based structure (IC50 value measured by cell-free assay not tested). A maximum effect of 85% apoptosis with 20 nM panobinostat in MOLT-4 cells and 80% apoptosis with 50 nM panobinostat in Reh cells can observed at 72h. Panobinostat can inhibit proliferation and cell-cycle progression in the two ALL cells. IC50 of panobinostat in anti-proliferation of MOLT-4 cells is approximately 5 nM and for Reh cells is approximately 20 nM. Compared with the control cells, panobinostat treatment for 24h (up to 50 nM) caused a 2- to 3-fold increase in the number of cells in the G2/M phase. Like other HDAC pan inhibitors, the hyperacetylation of H3K9 and H4K8, which are the biomarkers for the inhibition of class 1 HDACs, can be observed in MOLT-4 cells treated with panobinostat (10 - 50 nM) for 24h in a dose-dependent manner. Accompanied by that, the induction of p21 and p27 expression, as well as a decrease of c-Myc expression can also be found in the same time with 10 - 20 nM panobinostat. Echoing to the cell-arrest and growth inhibition, the apoptosis and DNA damage response genes, like GADD45A, GADD45B, GADD45G, FANCG, and FOXO3A can be increased robustly in the ALL cells after treatment with 50 nM panobinostat for 24h. These suggest that the growth inhibition effect of panobinostat may due to the apoptosis and DNA damage response caused by HDACs inhibition^[2]. Panobinostat in combination with bortezomiband dexamethasone is approved by FDA for the treatment for patients with multiple myeloma who receive prior treatment with bortezomib and an immunomodulatory (IMiD) agent^[3].
• 作用机制Panobinostat has hydroxamate-based structure, which can chelate the Zn2+ ion of HDACs^[2].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  769-P	10/25/50 nM	Growth Inhibition Assay	48 h	inhibits cell growth in a dose dependent manner synergistically with ritonavir	25279191
  769-P	50 nM	Apoptosis Assay	48 h	induces cell apoptosis combined ritonavir	25279191
  769-P	25/50 nM	Growth Inhibition Assay	48 h	inhibits cell growth in a dose dependent manner synergistically with bortezomib	25176354

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• 动物研究
  剂量	Mice[4] (i.p.): 5 mg/kg- 20 mg/kg
  给药途径	i.p.
  动物药代数据	Animal Rats[5] Dogs[5] Dose 10 mg/kg 0.5 mg/kg Administration i.v. Cmax 1016 ng/ml 76.7 ng/ml T1/2 3.81 ± 1.39 h 16 h AUC0→∞ 155 ng·h/ml CL 22.1 ± 3.49 L/h/kg 3.3 L/h/kg Tmax 0.083 h Vss 40.2 ± 16 L/kg 42 L/kg AUCinf 459 ± 70 ng·h/ml

• 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
  NCT02506959	Plasma Cell Leukemia ... more >> Plasmacytoma Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma Collapse <<	Phase 2	Recruiting	September 14, 2019	United States, Texas ... more >> M D Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Contact: Yago L. Nieto    713-792-8750    ynieto@mdanderson.org    Principal Investigator: Yago L. Nieto Collapse <<
  NCT00449761	Leukemia, Myeloid, Chronic	Phase 2 Phase 3	Completed	-	-
  NCT01055483	Acute Myeloid Leukemia	Phase 1	Completed	-	France ... more >> Novartis Investigative Site Paris Cedex 4, France, 75181 Novartis Investigative Site Paris, France, 75475 Germany Novartis Investigative Site Dresden, Germany, 01307 Novartis Investigative Site Frankfurt, Germany, 60590 Novartis Investigative Site Hannover, Germany, 30625 Novartis Investigative Site Ulm, Germany, 89081 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] Scuto A, Kirschbaum M, et al. The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells. Blood. 2008 May 15;111(10):5093-100.

  [3] Raedler LA, et al. Farydak (Panobinostat): First HDAC Inhibitor Approved for Patients with Relapsed Multiple Myeloma. Am Health Drug Benefits. 2016 Mar;9(Spec Feature):84-7.

  [4] Ocio EM, Vilanova D, et al. In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica. 2010 May;95(5):794-803.

  [5] 205353Orig1s000PharmR

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