Zhiqing Liu1, Bing Tian2, Haiying Chen1, Pingyuan Wang1, Allan R Brasier3, Jia Zhou4. 1. Chemical Biology Program, Department of Pharmacology and Toxicology, Galveston, TX, 77555, USA. 2. Department of Internal Medicine, Galveston, TX, 77555, USA; Sealy Center for Molecular Medicine, Galveston, TX, 77555, USA. 3. Department of Internal Medicine, Galveston, TX, 77555, USA; Sealy Center for Molecular Medicine, Galveston, TX, 77555, USA; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, 77555, USA. 4. Chemical Biology Program, Department of Pharmacology and Toxicology, Galveston, TX, 77555, USA; Sealy Center for Molecular Medicine, Galveston, TX, 77555, USA; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, 77555, USA. Electronic address: jizhou@utmb.edu.
Abstract
A series of diverse small molecules have been designed and synthesized through structure-based drug design by taking advantage of fragment merging and elaboration approaches. Compounds ZL0420 (28) and ZL0454 (35) were identified as potent and selective BRD4 inhibitors with nanomolar binding affinities to bromodomains (BDs) of BRD4. Both of them 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. Both compounds 28 and 35 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, they 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.
A series of diverse small molecules have been designed and synthesized through structure-based drug design by taking advantage of fragment merging and elaboration approaches. Compounds n class="Chemical">ZL0420 (28) and ZL0454 (35) were identified as potent and selective BRD4 inhibitors with nanomolar binding affinities to bromodomains (BDs) of BRD4. Both of them 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. Both compounds 28 and 35 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, they 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.
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