6MAU
Crystal structure of human BRD4(1) in complex with CN210 (compound 19)
Summary for 6MAU
| Entry DOI | 10.2210/pdb6mau/pdb |
| Descriptor | Bromodomain-containing protein 4, 1-(4-{6-(3,5-dimethyl-1,2-oxazol-4-yl)-4-[(3S)-3-phenylmorpholin-4-yl]quinazolin-2-yl}-1H-pyrazol-1-yl)-2-methylpropan-2-ol, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | brd4(1), protein binding |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 15946.30 |
| Authors | Nadupalli, A.,Fontano, E.,Connors, C.R.,Chan, S.G.,Olland, A.M.,Lakshminarasimhan, D.,White, A.,Suto, R.K. (deposition date: 2018-08-28, release date: 2019-04-03, Last modification date: 2024-03-13) |
| Primary citation | Yang, S.M.,Yoshioka, M.,Strovel, J.W.,Urban, D.J.,Hu, X.,Hall, M.D.,Jadhav, A.,Maloney, D.J. Lead optimization and efficacy evaluation of quinazoline-based BET family inhibitors for potential treatment of cancer and inflammatory diseases. Bioorg. Med. Chem. Lett., 29:1220-1226, 2019 Cited by PubMed Abstract: Extensive optimization of quinazoline-based lead 8 is described. The structure-activity relationship studies indicate the S-configuration is preferred for the phenylmorpholine substitution. Together with incorporation of a (2-hydroxyl-2-methylpropyl)pyrazole moiety at the 2-position leads to analogs with comparable potency and marked improvement in the pharmacokinetic profile over our previously reported lead compounds. Further in vivo efficacy studies in Kasumi-1 xenograft mouse model demonstrates that the selected inhibitors are well tolerated and highly efficacious in the inhibition of tumor growth. Additionally, the representative analog 19 also demonstrated significant improvement of arthritis severity in a collagen-induced arthritis (CIA) mouse model. These results indicate potential use of these quinazoline-based BET inhibitors for treatment of cancer and inflammatory diseases. A brief discussion of the co-crystallized structure of 19 with BRD4 (BD1) is also highlighted. PubMed: 30905542DOI: 10.1016/j.bmcl.2019.03.014 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.11 Å) |
Structure validation
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