TY - JOUR
T1 - Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation
AU - Liu, Zhiqing
AU - Tian, Bing
AU - Chen, Haiying
AU - Wang, Pingyuan
AU - Brasier, Allan
AU - Zhou, Jia
N1 - Funding Information:
This work was supported, in part, by NIH grants ( NIAID AI062885 , UL1TR001439 , P30 DA028821 ), UTMB Technology Commercialization Program , and Sanofi Innovation Awards (iAwards) as well as Fellowship award entitled “Drug Discovery of BRD4 Inhibitors for the Treatment of Inflammatory Bowel Disease” (Identifier: 548813 ) from the Crohn's & Colitis Foundation of America (ZL). Core laboratory support was provided by the UTMB Histopathology Core. We want to thank Drs. Lawrence C. Sowers at the Department of Pharmacology as well as Dr. Tianzhi Wang at the NMR core facility of UTMB for the NMR spectroscopy assistance, and Dr. Xuemei Luo at UTMB mass spectrometry core with funding support from UT system proteomics network for the HRMS analysis.
Publisher Copyright:
© 2018 Elsevier Masson SAS
PY - 2018/5/10
Y1 - 2018/5/10
N2 - 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.
AB - 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.
KW - Airway inflammation
KW - Bromodomain-containing protein 4 (BRD4)
KW - Bromodomains
KW - Immune response genes
KW - Structure-based drug design
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U2 - 10.1016/j.ejmech.2018.04.006
DO - 10.1016/j.ejmech.2018.04.006
M3 - Article
C2 - 29649741
AN - SCOPUS:85045033477
SN - 0223-5234
VL - 151
SP - 450
EP - 461
JO - CHIM.THER.
JF - CHIM.THER.
ER -