8WIU
Bromodomain and Extra-terminal Domain (BET) BRD4
Summary for 8WIU
| Entry DOI | 10.2210/pdb8wiu/pdb |
| Descriptor | Isoform C of Bromodomain-containing protein 4, 7-[5-[1-(cyclopropylmethyl)-3,5-dimethyl-pyrazol-4-yl]pyridin-3-yl]-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 | 15084.46 |
| Authors | |
| Primary citation | Chen, X.,Wu, T.,Du, Z.,Kang, W.,Xu, R.,Meng, F.,Liu, C.,Chen, Y.,Bao, Q.,Shen, J.,You, Q.,Cao, D.,Jiang, Z.,Guo, X. Discovery of a brain-permeable bromodomain and extra terminal domain (BET) inhibitor with selectivity for BD1 for the treatment of multiple sclerosis. Eur.J.Med.Chem., 265:116080-116080, 2023 Cited by PubMed Abstract: Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease and lacks effective therapeutic agents. Dysregulation of transcription mediated by bromodomain and extra-terminal domain (BET) proteins containing two different bromodomains (BD1 and BD2) is an important factor in multiple diseases, including MS. Herein, we identified a series of BD1-biased inhibitors, in which compound 16 showed nanomolar potency for BD1 (K = 230 nM) and a 60-fold selectivity for BRD4 BD1 over BD2. The co-crystal structure of BRD4 BD1 with 16 indicated that the hydrogen bond interaction of 16 with BD1-specific Asp145 is important for BD1 selectivity. 16 showed favorable brain distribution in mice and PK properties in rats. 16 was able to inhibit microglia activation and had significant therapeutic effects on EAE mice including improvement of spinal cord inflammatory conditions and demyelination protection. Overall, these results suggest that brain-permeable BD1 inhibitors have the potential to be further investigated as therapeutic agents for MS. PubMed: 38142510DOI: 10.1016/j.ejmech.2023.116080 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.4 Å) |
Structure validation
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