ZL0454 (ZL-0454), an analog of ZL0420, is a novel potent and highly selective inhibitor of BRD4 (Bromodomain-Containing Protein 4) with nanomolar binding affinities to bromodomains (BDs) of BRD4. ZL0454 can be well docked into the acetyl-lysine (KAc) binding pocket of BRD4, forming key interactions including the critical hydrogen bonds with Asn140 directly and Tyr97 indirectly via a H2O molecule. ZL0454 exhibited submicromolar potency of inhibiting the TLR3-dependent innate immune gene program, including ISG54, ISG56, IL-8, and Groβ genes in cultured human small airway epithelial cells (hSAECs). More importantly, ZL0454 also demonstrated potent efficacy reducing airway inflammation in a mouse model with low toxicity, indicating a proof of concept that BRD4 inhibitors may offer the therapeutic potential to block the viral-induced airway inflammation.

Physicochemical Properties

Molecular Formula	C18H22N4O3S
Molecular Weight	374.457282543182
Exact Mass	374.141
CAS #	2229042-77-5
Related CAS #	2229042-77-5 (ZL0454);
PubChem CID	137285009
Appearance	Brown to reddish brown solid powder
LogP	3.3
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	5
Heavy Atom Count	26
Complexity	578
Defined Atom Stereocenter Count	0
SMILES	S(C1C=CC(=CC=1)/N=N/C1C=C(C)C(=CC=1N)O)(NC1CCCC1)(=O)=O
InChi Key	IRKMSULWLDLTIK-UHFFFAOYSA-N
InChi Code	InChI=1S/C18H22N4O3S/c1-12-10-17(16(19)11-18(12)23)21-20-13-6-8-15(9-7-13)26(24,25)22-14-4-2-3-5-14/h6-11,14,22-23H,2-5,19H2,1H3
Chemical Name	(E)-4-((2-Amino-4-hydroxy-5-methylphenyl)diazenyl)-N-cyclopentylbenzenesulfonamide
Synonyms	ZL0454; ZL 0454; ZL-0454
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

References

:Am J Respir Cell Mol Biol.2018 Aug 28. doi: 10.1165/rcmb.2017-0445OC;Eur J Med Chem.2018 May 10;151:450-461.

Solubility Data

Solubility (In Vitro)

DMSO: >10 mM Water:N/A Ethanol:N/A

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.68 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 (6.68 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.6705 mL	13.3526 mL	26.7051 mL
	5 mM	0.5341 mL	2.6705 mL	5.3410 mL
	10 mM	0.2671 mL	1.3353 mL	2.6705 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.