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
Herein, we describe a systematic SAR- and SPR-investigation of the peptidomimetic hydroxy-proline based VHL-ligand VH032, from which most to-date published VHL-targeting PROTACs have been derived. This study provides for the first time a consistent data set which allows for direct comparison of structural variations including those which were so far hidden in patent literature. The gained knowledge about improved VHL binders was used to design a small library of highly potent BRD4-degraders comprising different VHL exit vectors. Newly designed degraders showed favorable molecular properties and significantly improved degradation potency compared to MZ1.
Systematic Potency & Property Assessment of VHL Ligands and Implications on PROTAC Design.,Krieger J, Sorell FJ, Wegener AA, Leuthner B, Machrouhi-Porcher F, Hecht M, Leibrock EM, Mueller JE, Eisert J, Hartung IV, Schlesiger S ChemMedChem. 2023 Feb 7. doi: 10.1002/cmdc.202200615. PMID:36749883[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
- ↑ Krieger J, Sorrell FJ, Wegener AA, Leuthner B, Machrouhi-Porcher F, Hecht M, Leibrock EM, Müller JE, Eisert J, Hartung IV, Schlesiger S. Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design. ChemMedChem. 2023 Feb 7:e202200615. PMID:36749883 doi:10.1002/cmdc.202200615
