| Structural highlights
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
BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was co-crystalized with BRD4, yielding a 1.56 A resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors.
Biased multicomponent reactions to develop novel bromodomain inhibitors.,McKeown MR, Shaw DL, Fu H, Liu S, Xu X, Marineau JJ, Huang Y, Zhang X, Buckley DL, Kadam A, Zhang Z, Blacklow SC, Qi J, Zhang W, Bradner JE J Med Chem. 2014 Oct 14. PMID:25314271[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
- ↑ McKeown MR, Shaw DL, Fu H, Liu S, Xu X, Marineau JJ, Huang Y, Zhang X, Buckley DL, Kadam A, Zhang Z, Blacklow SC, Qi J, Zhang W, Bradner JE. Biased multicomponent reactions to develop novel bromodomain inhibitors. J Med Chem. 2014 Oct 14. PMID:25314271 doi:http://dx.doi.org/10.1021/jm501120z
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