Last update 01 Nov 2024

BRD4 x BRPF2

Last update 01 Nov 2024

Basic Info

Related Targets

BRD4BRPF2

Drugs associated with BRD4 x BRPF2

CVG-101

Target

BRD4 x BRPF2

Mechanism

BRD4 inhibitors [+1]

Active Org.-

Originator Org.

Convergene LLC

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with BRD4 x BRPF2

100 Translational Medicine associated with BRD4 x BRPF2

0 Patents (Medical) associated with BRD4 x BRPF2

Literatures (Medical) associated with BRD4 x BRPF2

19 Sep 2023·ACS Omega

Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations

Article

Author: Yang, Yuhan ; Zou, Zhiyan ; Zhou, Yan ; Lu, Zhou ; Hu, Yan ; Shi, Mingsong ; Jing, Meng ; Zheng, Xueting ; Chen, Tingting ; Li, Xiaoan ; Lei, Dan ; Yang, Pei ; Yin, Yuan ; Liang, Yuanyuan

Bromodomain and extra-terminal domain (BET) proteins play an important role in epigenetic regulation and are linked to several diseases; therefore, they are interesting targets. BET has two bromodomains: bromodomain 1 (BD1) and BD2. Selective targeting of BD1 or BD2 may produce different activities and greater effects than pan-BD inhibitors. However, the selective mechanism of the specific core must be studied at the atomic level. This study determined the effectiveness of pyrrolopyridone analogues to selectively inhibit BD2 using a pan-BD inhibitor (ABBV-075) and a selective-BD2 inhibitor (ABBV-744). Molecular dynamics simulations and calculations of binding free energies were used to systematically study the selectivity of BD2 inhibition by the pyrrolopyridone analogues. Overall, the pyrrolopyridone analogue inhibitors targeting BD2 interacted mainly with the following amino acid pairs between bromodomain-containing protein 4 (BRD4)-BD1 and BRD4-BD2 complexes: I146/V439, N140/N433, D144/H437, P82/P375, V87/V380, D88/D381, and Y139/Y432. The pyrrolopyridone analogues targeting BRD4-BD2 were divided into five regions based on selectivity mechanism. These results suggest that the R3 and R5 regions of pyrrolopyridone analogues can be modified to improve the selectivity between BRD4-BD1 and BRD4-BD2. The selectivity of BD2 inhibition by pyrrolopyridone analogues can be used to design novel BD2 inhibitors based on a pyrrolopyridone core.

12 Jan 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

Physachenolide C is a Potent, Selective BET Inhibitor

Q1 · MEDICINE

Article

Author: Xu, Ya-Ming ; Chapman, Eli ; Sivinski, Jared ; Horton, Nancy C. ; Gunatilaka, A. A. Leslie ; Zerio, Christopher J. ; Ambrose, Andrew J. ; Clarkson, Michael W. ; Villa-Celis, Luis ; Wijeratne, E. M. Kithsiri ; Ghadirian, Niloofar ; Zhang, Donna D. ; Ngo, Duc T. ; Fromme, Raimund

A pulldown using a biotinylated natural product of interest in the 17β-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), identified the bromodomain and extra-terminal domain (BET) family of proteins (BRD2, BRD3, and BRD4), readers of acetyl-lysine modifications and regulators of gene transcription, as potential cellular targets. BROMOscan bromodomain profiling and biochemical assays support PCC as a BET inhibitor with increased selectivity for bromodomain (BD)-1 of BRD3 and BRD4, and X-ray crystallography and NMR studies uncovered specific contacts that underlie the potency and selectivity of PCC toward BRD3-BD1 over BRD3-BD2. PCC also displays characteristics of a molecular glue, facilitating proteasome-mediated degradation of BRD3 and BRD4. Finally, PCC is more potent than other withanolide analogues and gold-standard pan-BET inhibitor (+)-JQ1 in cytotoxicity assays across five prostate cancer (PC) cell lines regardless of androgen receptor (AR)-signaling status.

05 Jul 2022·Biochemistry

Alternative Mechanisms for DNA Engagement by BET Bromodomain-Containing Proteins

Article

Author: Pomerantz, William C. K. ; Ayoub, Alex ; Dou, Yali ; Zahid, Huda ; Kalra, Prakriti

Epigenetic reader domains regulate chromatin structure and modulate gene expression through the recognition of post-translational modifications on histones. Recently, reader domains have also been found to harbor double-stranded (ds) DNA-binding activity, which is as functionally critical as histone association. Here, we explore the dsDNA recognition of the N-terminal bromodomain of the bromodomain and extra-terminal (BET) protein, BRD4. Using protein-observed ¹⁹F NMR, ¹H-¹⁵N HSQC NMR, electrophoretic mobility shift assays (EMSA), and competitive-inhibition assays, we establish the binding surface of dsDNA and find it to be largely overlapping with the acetylated histone (KAc)-binding site. Rather than engaging in electrostatic contacts, we find dsDNA to interact competitively within the KAc-binding pocket. These interactions are distinct from the highly homologous BET bromodomain, BRDT. Nine additional bromodomains have also been characterized for interacting with dsDNA, including tandem BET bromodomains. Together, these studies help establish a binding model for dsDNA interactions with BRD4 bromodomains and elucidate the chromatin-recognition mechanisms of the BRD4 protein for regulating gene expression.

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