HDAC-IN-4 (also known as CXD101, AZD9468) is a novel and potent inhibitor of histone deacetylase (HDAC) with potential anticancer and immunomodulatory activity. It is taken from the 20070426 patent WO/2007045844 A1. Learning and memory as well as synaptic plasticity have been linked to the family of enzymes known as histone deacetylases (HDACs), which play a role in epigenetic regulation. The structures of HDAC-IN-4 and mocetinostat, MS-275, and JNJ-26481585 are similar.

Physicochemical Properties

Molecular Formula	C24H29N5O
Molecular Weight	403.519964933395
Exact Mass	403.25
Elemental Analysis	C, 71.44; H, 7.24; N, 17.36; O, 3.96
CAS #	934828-12-3
Related CAS #	934828-12-3
PubChem CID	16225380
Appearance	White to off-white solid powder
LogP	2.9
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	5
Heavy Atom Count	30
Complexity	556
Defined Atom Stereocenter Count	0
InChi Key	JHDZMASHNBKTPS-UHFFFAOYSA-N
InChi Code	InChI=1S/C24H29N5O/c1-17-21(15-28(2)27-17)16-29-13-11-19(12-14-29)18-7-9-20(10-8-18)24(30)26-23-6-4-3-5-22(23)25/h3-10,15,19H,11-14,16,25H2,1-2H3,(H,26,30)
Chemical Name	N-(2-aminophenyl)-4-[1-[(1,3-dimethylpyrazol-4-yl)methyl]piperidin-4-yl]benzamide
Synonyms	CXD-101; AZD 9468; CXD101; AZD-9468; CXD 101; HDAC-IN-4; AZD9468
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
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

Targets	HDAC1 ( IC50 = 63 nM ); HDAC3 ( IC50 = 550 nM ); HDAC2 ( IC50 = 570 nM )
ln Vitro	Zabadinostat has been examined in vitro using cell lines from non-Hodgkin lymphoma, colon, lung, and myeloma, with IC50 values ranging from 0.2 to 15 μM[2].
ln Vivo	Zabadinostat significantly reduces the size of tumors in murine xenograft lung (A549a) and colon (HT29) models when administered at a dose of 50 mg/kg. It has been discovered that reduced HDAC enzyme activity and elevated histone acetylation are linked to tumor reductions[2]. For Zabadinostat, terminal half-lives are 6 and 8 hours, respectively, and peak plasma concentrations (Cmax) are reached 1 to 2 hours after oral dosing in murine and canine models. Tissue radioactivity peaked three to six hours after oral [14C]-Zabadinostat (1.6 mg/kg; 4 μmol/kg) was administered to mice. There was still Zabadinostat-related material in the tissue twenty-one days after the dose[2].
References	[1]. Predictive biomarkers for disease sensitivity in lymphoma - the holy grail for HDAC inhibitors? Oncotarget. 2018 Dec 18;9(99):37280-37281. [2]. A phase 1 study to assess the safety, tolerability, and pharmacokinetics of CXD101 in patients with advanced cancer. Cancer. 2019 Jan 1;125(1):99-108.
Additional Infomation	CXD101 is under investigation in clinical trial NCT03873025 (A Study of CXD101 in Combination With Pembrolizumab for Relapsed or Refractory Diffuse Large B-cell Lymphoma). Zabadinostat is a novel histone deacetylase (HDAC) inhibitor with potential antineoplastic activity. Although the exact therapeutic mechanism of action for CXD101 is not known, oral administration of this agent should inhibit the catalytic activity of HDAC, which results in an accumulation of highly acetylated histones, followed by the induction of chromatin remodeling and an altered pattern of gene expression. HDAC, a family of enzymes upregulated in many tumor types, deacetylates chromatin-associated histone proteins.

Solubility Data

Solubility (In Vitro)

DMSO: ≥ 31 mg/mL Water: <1 mg/mL Ethanol: N/A

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.20 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 (6.20 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (6.20 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 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	2.4782 mL	12.3910 mL	24.7819 mL
	5 mM	0.4956 mL	2.4782 mL	4.9564 mL
	10 mM	0.2478 mL	1.2391 mL	2.4782 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.