A4090-5mg | JNJ-26481585 [875320-29-9] Biotrend

Background

JNJ-26481585 is a novel histone deacetylase (HDAC) inhibitor that exerts a strong potency towards class I HDAC (including HDAC1, HDAC2 and HDAC3), with values of inhibition constant IC₅₀ of 0.11, 0.33 and 4.8 nmol/L respectively, leading to strong anti-proliferative activities (IC₅₀ ranging from 3.1 to 246 nmol/L) against a broad range of cancer cell lines including lung, breast, colon, prostate, brain and overian cancer cell lines. Recent study results have shown that JNJ-26481585 strongly induce the HDAC1-suppressed p21^waf1,cip1promoter in vivo, histone H3 acetylation in tumor tissue and apoptosis in human colon cancer cell lines (both APC wild-type and mutant) in vitro.

Reference

Arts J, King P, Mariën A, Floren W, Beliën A, Janssen L, Pilatte I, Roux B, Decrane L, Gilissen R, Hickson I, Vreys V, Cox E, Bol K, Talloen W, Goris I, Andries L, Du Jardin M, Janicot M, Page M, van Emelen K, Angibaud P. JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin Cancer Res. 2009;15(22):6841-6851

Product Citation

1. Sauradip Chaudhuri, Martha Fowler, et al. "β-Cyclodextrin-Poly (β-Amino Ester) Nanoparticles Are a Generalizable Strategy for High Loading and Sustained Release of HDAC Inhibitors." ChemRxiv. Mar 27.2020
2. Zhou H, Mondal A, et al. "Time-Dependent Effects of POT1 Knockdown on Proliferation, Tumorigenicity, and HDACi Response of SK-OV3 Ovarian Cancer Cells." Biomed Res Int. 2018 Feb 6;2018:7184253. PMID:29546066
3. Householder KT, DiPerna DM, et al. "pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma." Colloids Surf B Biointerfaces. 2018 Feb 24;166:37-44. PMID:29533842

Chemical Properties

Storage	Store at -20°C
M.Wt	394.47
Cas No.	875320-29-9
Formula	C₂₁H₂₆N₆O₂
Synonyms	JNJ26481585
Solubility	insoluble in H2O; insoluble in EtOH; ≥19.2 mg/mL in DMSO
Chemical Name	N-hydroxy-2-(4-((((1-methyl-1H-indol-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide
SDF	Download SDF
Canonical SMILES	CN(C=C1CNCC2CCN(C3=NC=C(C(NO)=O)C=N3)CC2)C4=C1C=CC=C4
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Kinase experiment [1]:
Inhibitory activities	Recombinant HDAC activity assays were done by Reaction Biology Corporation. In all cases, full-length HDAC proteins were expressed using baculovirus-infected Sf9 cells. In addition, HDAC3 was coexpressed as a complex with human NCOR2. For assessing activity of HDAC1-containing cellular complexes, immunoprecipitated HDAC1 complexes were incubated with an [3H]acetyllabeled fragment of histone H4 peptide [biotin-(6-aminohexanoic)Gly-Ala-(acetyl[3H])Lys-Arg-His-Arg-Lys-Val-NH2]. Equal amounts of HDAC1 were immunoprecipitated as indicated by Western blot analysis. HDAC1 activity results are presented as mean ± SD of three independent experiments on a single lysate.
Cell experiment [1]:
Cell lines	Non-small cell lung carcinoma (NSCLC) cell lines; hematologic cell lines; human tumor cells; human A2780 ovarian carcinoma cells.
Preparation method	Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
Reaction Conditions	cell proliferation: 72 h, apoptosis assays: 24, 48, and 96 h.
Applications	In all lung, breast, colon, prostate, brain, and ovarian tumor cell lines tested, JNJ-26481585 inhibits cell proliferation with IC50 values of 3.1-246 nM. In A2780 ovarian tumor cells, JNJ-26481585 (3-300 nM) significantly and dose-dependently increases the amount of cells positive for Annexin V, which indicates apoptosis.
Animal experiment [1]:
Animal models	Male athymic nu/nu CD-1 mice injected s.c. with human A2780-p21waf1,cip1 ZsGreen ovarian tumors cells
Dosage form	10 mg/kg i.p. and 40 mg/kg p.o.; once daily for 3 d.
Preparation method	Formulated at 2 mg/mL in 20% hydroxypropyl-β-cyclodextrin (final pH 8.7).
Applications	In the HDAC1-responsive A2780 ovarian tumor screening model, JNJ-26481585 induces a bright and intense fluorescence, which is not uniformly distributed throughout the tissue and fully predicts tumor growth inhibition. Also, JNJ-26481585 induces potent H3 acetylation in the tumor tissue. In HCT116 colon xenografts, JNJ-26481585 (once daily, 10 mg/kg i.p.) for 14 days inhibits tumor volume by 76% and induces H3 acetylation.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. Arts J, King P, Marin A, et al. JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin Cancer Res, 2009, 15(22): 6841-6851.

Biological Activity

Description	Quisinostat (JNJ-26481585) is a novel second-generation inhibitor of HDAC with highest potency for HDAC1 with IC50 of 0.11 nM.
Targets	HDAC1	HDAC2	HDAC4	HDAC10	HDAC11
IC50	0.11 nM	0.33 nM	0.64 nM	0.46 nM	0.37 nM