7mcf

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CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-{3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Structural highlights

7mcf is a 2 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 2.19Å
Ligands:
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

We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.

Development of BET inhibitors as potential treatments for cancer: A search for structural diversity.,Hill MD, Fang H, Tokarski J, Fanslau C, Haarhoff Z, Huang C, Kramer M, Menard K, Monereau L, Morrison J, Ranasinghe A, Shields EE, Tye CK, Westhouse R, Everlof G, Sheriff S, Yan C, Marsilio F, Zhang L, Zvyaga T, Lee F, Gavai AV, Degnan AP Bioorg Med Chem Lett. 2021 May 13;44:128108. doi: 10.1016/j.bmcl.2021.128108. PMID:33991625^[3]

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

References

↑ 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
↑ 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
↑ Hill MD, Fang H, Tokarski J, Fanslau C, Haarhoff Z, Huang C, Kramer M, Menard K, Monereau L, Morrison J, Ranasinghe A, Shields EE, Tye CK, Westhouse R, Everlof G, Sheriff S, Yan C, Marsilio F, Zhang L, Zvyaga T, Lee F, Gavai AV, Degnan AP. Development of BET inhibitors as potential treatments for cancer: A search for structural diversity. Bioorg Med Chem Lett. 2021 May 13;44:128108. doi: 10.1016/j.bmcl.2021.128108. PMID:33991625 doi:http://dx.doi.org/10.1016/j.bmcl.2021.128108