8ibq

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Bromodomain and Extra-terminal Domain (BET) BRD4

Structural highlights

8ibq is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.45Å
Ligands:OWO
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.[1] [2]

Function

BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).

Publication Abstract from PubMed

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 1 from an in-house compound library, iterative optimization resulted in the potent BET inhibitor DDO-8926 with a unique binding mode and a novel chemical structure. DDO-8926 exhibits excellent BET selectivity and favorable drug-like properties. In mice with spared nerve injury, DDO-8926 significantly alleviated mechanical hypersensitivity by inhibiting pro-inflammatory cytokine expression and reducing excitability. Collectively, these results implicate that DDO-8926 is a promising agent for the treatment of NP.

Discovery of 1H-Imidazo[4,5-b]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain.,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 J Med Chem. 2023 Jul 13;66(13):8725-8744. doi: 10.1021/acs.jmedchem.3c00372. Epub , 2023 Jun 29. PMID:37382379[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
  2. ↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
  3. ↑ 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 1H-Imidazo[4,5-b]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain. J Med Chem. 2023 Jul 13;66(13):8725-8744. PMID:37382379 doi:10.1021/acs.jmedchem.3c00372

Contents


PDB ID 8ibq

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OCA

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