ZL0420 是有效且选择性的 BET 溴结构域 4 (BRD4) 抑制剂，对 BRD4 的溴结构域 (BD) 具有纳摩尔结合亲和力。ZL0420 对 BRD4 BD1和 BRD4 BD2 的IC50分别为 27 nM 和 32 nM。

ZL0420 is a potent and selective bromodomain-containing protein 4 ( BRD4 ) inhibitor with nanomolar binding affinities to bromodomains (BDs) of BRD4. ZL0420 has IC 50 values of 27 nM against BRD4 BD1 and 32 nM against BRD4 BD2.

ZL0420 is well docked into the acetyl-lysine (KAc) binding pocket of BRD4 that forms key interactions including the critical hydrogen bonds with Asn140 directly and Tyr97 indirectly via a H 2 O molecule. ZL0420 exhibits 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) with IC 50 s of 0.49-0.86 μM [1].

ZL0420 displays potent efficacy reducing airway inflammation in a mouse model with low toxicity. ZL0420 displays highly potent and almost completely blocks the profound accumulation of neutrophils around the small and medium sized airways induced by poly(I:C) administration [1].

Male C57BL6/J mice housed under pathogen-free conditions with food and water ad libitum.?C57BL/6 mice were pre-treated in the absence or presence of the indicated BRD4 inhibitors [10 mg/kg body weight, via the intraperitoneal route] one day prior to poly stimulation.?The next day, animals were given another dose of BRD4 inhibitor immediately followed by intranasal ?administration of phosphate-buffered saline (PBS, 50 μL) or poly (300 μg dissolved in 50 μL PBS).?One day later, the mice were euthanized.?The bronchoalveolar lavage fluid (BALF) and lung tissues of treated mice were collected for further analysis.?Compounds were first dissolved in DMSO and further diluted in 10% hydroxypropyl β-cyclodextrin in PBS to appropriate concentration prior to intraperitoneal administration.

2229039-45-4

C16H16N4O2

296.33

ZL0420

DMSO:59 mg/mL (199.11 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years