8IBQ

Bromodomain and Extra-terminal Domain (BET) BRD4

Summary for 8IBQ

• Entry DOI: 10.2210/pdb8ibq/pdb
• Descriptor: Bromodomain-containing protein 4, 7-[2-fluoranyl-3-(1,3,5-trimethylpyrazol-4-yl)phenyl]-1~{H}-imidazo[4,5-b]pyridine (3 entities in total)
• Functional Keywords: binds acetylated lysine residues, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 14974.32

Authors

Cao, D.,Zhiyan, D.,Xiong, B. (deposition date: 2023-02-10, release date: 2023-10-04)

Primary citation

Chen, X.,Cao, D.,Liu, C.,Meng, F.,Zhang, Z.,Xu, R.,Tong, Y.,Xin, Y.,Zhang, W.,Kang, W.,Bao, Q.,Shen, J.,Xiong, B.,You, Q.,Jiang, Z.
Discovery of 1 H -Imidazo[4,5- b ]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain.
J.Med.Chem., 66:8725-8744, 2023

PubMed Abstract: Neuropathic pain (NP) is an intolerable pain syndrome that arises from continuous inflammation and excitability after nerve injury. Only a few NP therapeutics are currently available, and all of them do not provide adequate pain relief. Herein, we report the discovery of a selective and potent inhibitor of the bromodomain and extra-terminal (BET) proteins for reducing neuroinflammation and excitability to treat NP. Starting with the screening hit from an in-house compound library, iterative optimization resulted in the potent BET inhibitor with a unique binding mode and a novel chemical structure. exhibits excellent BET selectivity and favorable drug-like properties. In mice with spared nerve injury, significantly alleviated mechanical hypersensitivity by inhibiting pro-inflammatory cytokine expression and reducing excitability. Collectively, these results implicate that is a promising agent for the treatment of NP.

PubMed: 37382379
DOI: 10.1021/acs.jmedchem.3c00372

Experimental method

X-RAY DIFFRACTION (1.45 Å)