生物活性

• 靶点	HDAC6 IC50:5nM

• 描述There are 18 mammalian HDACs, HDAC 1 - 11 and sirt 1 - 7. One of the member, HDAC6 can target specific substrates like HSP90 andα-tubulin which involve in protein trafficking and degradation or cell shape and migration, thus participates in the pathways relating to neurodegenerative diseases, cancer, and immunology^[1]. ACY-1215, also called Rocilinostat, is a potent and selective HDAC6 inhibitor with IC50 value of 4.7 nM (measured by HDAC enzymatic assays), while exhibits minimal inhibition on HDAC4, HDAC5, HDAC7, HDAC9, HDAC11, Sirtuin1, and Sirtuin2 (IC50 > 1 μM) and slightly inhibits HDAC8 (IC50 = 0.1 μM). A dose-dependent increased acetylatedα-tubulin and no affecting acetylation of histones can be observed in MM.1S cells with treatment of ACY-1215 for 6 hours, which confirming the selective inhibition of ACY-1215 on low dose (0.62 μM). ACY-1215 (0 - 4 μM) in combination with bortezomib (0 - 5 nM) for 24 and 48 hours in MM.1S cells and for 48 hours in RPMI8226 cells induce synergistic anti-MM activity. This may due to ACY-1215 disrupting aggresome formation with increased levels of polyubiquitinated protein, then triggers the apoptosis by the induction of ER stress and UPR. And a significant therapeutic advantage was found by combining ACY-1215 (50 mg/kg, IP) with bortezomib (0.5 mg/kg, IV) compared with either agent alone for 3 weeks, which echoes the synergistic activity cellar study^[2]. ACY-1215 alone/ in combination with dexametrasone and either bortezomib or lenalidomide is currently under phase I, II clinical trials for multiple myeloma^[3].
• 作用机制ACY-1215 can monodentate Zn²⁺ of HDAC6 through its phenylhydroxamate structure^[4].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A-172	10 nM	Growth Inhibition Assay	24/48 h	inhibits cell growth time dependently	26150340
  CCL-119	-	Growth Inhibition Assay	48 h	IC50=1.7 μM	26116270
  H9	-	Growth Inhibition Assay	48 h	IC50=1.2 μM	26116270

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• 动物研究
  剂量	Mice[5] (i.p.): 50 mg/kg
  给药途径	i.p.
  动物药代数据	Animal Mice[2] Dose 50 mg/kg Administration i.p. Cmax 2133 ng/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
  NCT03176472	Diabetic Neuropathic Pain	Phase 2	Not yet recruiting	January 2021	-
  NCT02088398	Healthy	Phase 1	Completed	-	United States, Wisconsin ... more >> Covance Clinical Research Unit Incorporated Madison, Wisconsin, United States, 53704 Collapse <<
  NCT02189343	Multiple Myeloma	Phase 1	Active, not recruiting	January 30, 2019	United States, Texas ... more >> UT Southwestern Medical Center Simmons Comprehensive Cancer Center Dallas, Texas, United States, 75390-8852 CTRC at The UT Health Science Center at San Antonio San Antonio, Texas, United States, 78229 United States, Utah University of Utah Huntsman Cancer Institute Salt Lake City, Utah, United States, 84112 Collapse <<

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• 参考文献

• [1] Wang XX, Wan RZ, et al. Recent advances in the discovery of potent and selective HDAC6 inhibitors. Eur J Med Chem. 2018 Jan 1;143:1406-1418.

  [2] Santo L, Hideshima T, et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012 Mar 15;119(11):2579-89.

  [3] Seidel C, Schnekenburger M, et al. Histone deacetylase 6 in health and disease. Epigenomics. 2015;7(1):103-18.

  [4] Porter NJ, Mahendran A, et al. Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors. Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):13459-13464.

  [5] Selective Inhibition of HDAC6 with a New Prototype Inhibitor (ACY-1215) Overcomes Bortezomib Resistance In Multiple Myeloma (MM)

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