Nanatinostat (CHR-3996; Tractinostat; VRx-3996) is a novel, oral, and hydroxamic acid-based HDAC inhibitor (IC50 of 8 nM) with potential anticancer activity. By inhibiting HDAC, Nanatinostat causes an accumulation of highly acetylated histones, the induction of chromatin remodeling, and the selective transcription of tumor suppressor genes, ultimately leading to the inhibition of tumor cell division and the induction of tumor cell apoptosis.

Physicochemical Properties

Molecular Formula	C20H19FN6O2
Molecular Weight	394.402266740799
Exact Mass	393.16
CAS #	1256448-47-1
Related CAS #	914937-68-1 (racemic);1256448-47-1;1256448-48-2 (TFA);2648504-17-8 (hydrate); 1256448-48-2 (TFA); 1235859-13-8 (deleted);
PubChem CID	49857317
Appearance	White to off-white solid powder
LogP	1
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	5
Heavy Atom Count	29
Complexity	592
Defined Atom Stereocenter Count	2
SMILES	FC1C=CC2=C(C=1)C=CC(CNC1C3CN(C4N=CC(C(NO)=O)=CN=4)CC31)=N2
InChi Key	QRGHOAATPOLDPF-BYICEURKSA-N
InChi Code	InChI=1S/C20H19FN6O2/c21-13-2-4-17-11(5-13)1-3-14(25-17)8-22-18-15-9-27(10-16(15)18)20-23-6-12(7-24-20)19(28)26-29/h1-7,15-16,18,22,29H,8-10H2,(H,26,28)/t15-,16+,18?
Chemical Name	2-[(1S,5R)-6-[(6-fluoroquinolin-2-yl)methylamino]-3-azabicyclo[3.1.0]hexan-3-yl]-N-hydroxypyrimidine-5-carboxamide
Synonyms	Tractinostat VRx-3996 CHR 3996 VRx3996CHR-3996 CHR3996
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

References

Discovery of 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor. J Med Chem. 2010 Dec 23;53(24):8663-78.

Additional Infomation

Nanatinostat is under investigation in clinical trial NCT00697879 (Safety Study of the Histone Deacetylase Inhibitor, CHR-3996, in Patients With Advanced Solid Tumours). Nanatinostat is an orally bioavailable, second-generation hydroxamic acid-based inhibitor of histone deacetylase (HDAC), with potential antineoplastic activity. Nanatinostat targets and inhibits HDAC, resulting in an accumulation of highly acetylated histones, the induction of chromatin remodeling, and the selective transcription of tumor suppressor genes; these events result in the inhibition of tumor cell division and the induction of tumor cell apoptosis. This agent may upregulate HSP70 and downregulate anti-apoptotic Bcl-2 proteins more substantially than some first-generation HDAC inhibitors. HDACs, upregulated in many tumor cell types, are a family of metalloenzymes responsible for the deacetylation of chromatin histone proteins.

Solubility Data

Solubility (In Vitro)

DMSO : ~50 mg/mL (~126.77 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.34 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (6.34 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.5355 mL	12.6775 mL	25.3550 mL
	5 mM	0.5071 mL	2.5355 mL	5.0710 mL
	10 mM	0.2535 mL	1.2677 mL	2.5355 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.