Last update 01 Nov 2024

BRPF2 x ATAD2

Last update 01 Nov 2024

Basic Info

Related Targets

BRPF2ATAD2

Drugs associated with BRPF2 x ATAD2

BAY-850

Target

ATAD2 x BRPF2

Mechanism

ATAD2 inhibitors [+1]

Active Org.-

Originator Org.

Bayer AG

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with BRPF2 x ATAD2

100 Translational Medicine associated with BRPF2 x ATAD2

0 Patents (Medical) associated with BRPF2 x ATAD2

Literatures (Medical) associated with BRPF2 x ATAD2

01 Mar 2018·Journal of Cellular PhysiologyQ2 · BIOLOGY

Biological function and histone recognition of family IV bromodomain‐containing proteins

Q2 · BIOLOGY

Review

Author: Glass, Karen C. ; Lloyd, Jonathan T.

Bromodomain proteins function as epigenetic readers that recognize acetylated histone tails to facilitate the transcription of target genes. There are approximately 60 known human bromodomains, which are divided into eight sub‐families based on structural conservation. The bromodomain‐containing proteins in family IV include seven members (BRPF1, BRPF2, BRPF3, BRD7, BRD9, ATAD2, and ATAD2b). The bromodomains of each of these proteins recognize and bind acetyllysine residues on histone tails protruding from the nucleosome. However, the histone marks recognized by each bromodomain protein can be very different. The BRPF1 subunit of the MOZ histone acetyltransferase (HAT) recognizes acetylated histones H2AK5ac, H4K12ac, H3K14ac, H4K8ac, and H4K5ac. While the bromodomain of BRD7, a member of the SWI/SNF complex, was shown to preferentially recognize acetylated histones H3K9ac, H3K14ac, H4K8ac, H4K12ac, and H4K16ac. The bromodomains of BRPF2 and BRPF3 have similar sequences, and function as part of the HBO1 HAT complex, but there is limited data on which histone ligands they bind. Similarly, there is little known about the histone targets of the BRD9 and ATAD2b bromodomain proteins. Interestingly, the ATAD2 bromodomain was recently shown to preferentially bind to the di‐acetylated H4K5acK12ac mark found in newly synthesized histones following DNA replication. However, despite the physiological importance of the family IV bromodomains, little is known about how they function at the molecular or atomic level. In this review, we summarize our understanding of how family IV bromodomains recognize and select for acetyllysine marks and discuss the importance of acetylated histone recognition for their biological functions.

26 Oct 2017·Chemistry – A European JournalQ2 · CHEMISTRY

Synthesis and Demonstration of the Biological Relevance of sp³‐rich Scaffolds Distantly Related to Natural Product Frameworks

Q2 · CHEMISTRY

Article

Author: Nelson, Adam ; Foley, Daniel J. ; Doveston, Richard G. ; Talon, Romain ; Marsden, Stephen P. ; Aimon, Anthony ; Collins, Patrick M. ; von Delft, Frank ; Craven, Philip G. E. ; Churcher, Ian

AbstractThe productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A “top‐down” synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3‐rich scaffolds. The scaffolds have local natural product‐like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high‐throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space.

01 Oct 2017·Journal of Biological Chemistry

The ATAD2 bromodomain binds different acetylation marks on the histone H4 in similar fuzzy complexes

Article

Author: Langini, Cassiano ; Vitalis, Andreas ; Caflisch, Amedeo

Bromodomains are protein modules adopting conserved helix bundle folds. Some bromodomain-containing proteins, such as ATPase family AAA domain-containing protein 2 (ATAD2), isoform A, have attracted much interest because they are overexpressed in many types of cancer. Bromodomains bind to acetylated lysine residues on histone tails and thereby facilitate the reading of the histone code. Epigenetic regulators in general have been implicated as indicators, mediators, or causes of a large number of diseases and disorders. To interfere with or modulate these processes, it is therefore of fundamental interest to understand the molecular mechanisms by which epigenetic regulation occurs. Here, we present results from molecular dynamics simulations of a doubly acetylated histone H4 peptide bound to the bromodomain of ATAD2 (hereafter referred to as ATAD2A). These simulations revealed how the flexibility of ATAD2A's major loop, the so-called ZA loop, creates an adaptable interface that preserves the disorder of both peptide and loop in the bound state. We further demonstrate that the binding involves an almost identical average pattern of interactions irrespective of which acetyl mark is inserted into the pocket. In conjunction with a likely mechanism of electrostatically driven recruitment, our simulation results highlight how the bromodomain is built toward promiscuous binding with low specificity. In conclusion, the simulations indicate that disorder and electrostatic steering function jointly to recruit ATAD2A to the histone core and that these fuzzy interactions may promote cooperativity between nearby epigenetic marks.

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