Hitting a Moving Target: Simulation and Crystallography Study of ATAD2 Bromodomain Blockers

Dolbois, A.; Batiste, Laurent; Wiedmer, L.; Dong, Jing; Brütsch, Manuela M.; Huang, Danzhi; Deerain, Nicholas; Spiliotopoulos, Dimitrios; Cheng-Sánchez, Iván; Laul, Eleen; Nevado, Cristina; Śledź, P.; Caflisch, Amedeo

doi:10.1021/acsmedchemlett.0c00080

Cited by 9 publications

(11 citation statements)

References 33 publications

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“…This can be rationalized considering that the rim consists mainly of solvent-exposed loops. Also, there is an entropic penalty due to the conformational constraints imposed on the ZA loop by the bound inhibitors, 15 and the penalty might increase with the compound size. Growth of compound 4 was obtained through moieties of variable hydrophilicity, which importantly concur in defining logP and logD for 19 – 21 ( Table 1 ).…”

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confidence: 99%

Identification of a BAZ2A Bromodomain Hit Compound by Fragment Joining

Vedove

Cazzanelli

Corsi

et al. 2021

ACS Bio Med Chem Au

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The bromodomains of BAZ2A and BAZ2B (bromodomain adjacent to zinc finger domain proteins 2) are among the most hard to drug of the 61 human bromodomains. While little is known about the role of BAZ2B, there is strong evidence for the opportunity of targeting BAZ2A in various cancers. Here, a benzimidazole−triazole fragment that binds to the BAZ2A acetyl lysine pocket was identified by a molecular docking campaign and validated by competitive binding assays and X-ray crystallography. Another ligand was observed in close proximity by soaking experiments using the BAZ2A bromodomain preincubated with the benzimidazole−triazole fragment. The crystal structure of BAZ2A with the two ligands was employed to design a few benzimidazole−triazole derivatives with increased affinity. We also present the engineering of a BAZ2A bromodomain mutant for consistent, high-resolution crystallographic studies.

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confidence: 99%

Identification of a BAZ2A Bromodomain Hit Compound by Fragment Joining

Vedove

Cazzanelli

Corsi

et al. 2021

ACS Bio Med Chem Au

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“…It is a novel strategy to discover potent and selective ATAD2 inhibitors by coupling the ZA-loop rigidification and the rearrangement of the hydrophobic side chains. Based on the strategy, a potent ATAD2 inhibitor ( 8 ) was screened with a K d value of 15 μM 104 . The linker of acid amides formed two hydrogen bonds with ASN1064, and the piperazine group initiated a hydrogen interaction with ASP1071 located at the BC loop, which provided a promising scaffold to further optimize selective ATAD2 inhibitors.…”

Section: Targeting Atad2 With Pharmacological Small-molecule Compound...mentioning

confidence: 99%

ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target

Fu¹,

Zhang²,

Chen³

et al. 2023

Theranostics

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ATPase family AAA domain-containing protein 2 (ATAD2) has been widely reported to be a new emerging oncogene that is closely associated with epigenetic modifications in human cancers. As a coactivator of transcription factors, ATAD2 can participate in epigenetic modifications and regulate the expression of downstream oncogenes or tumor suppressors, which may be supported by the enhancer of zeste homologue 2. Moreover, the dominant structure (AAA + ATPase and bromine domains) can make ATAD2 a potential therapeutic target in cancer, and some relevant small-molecule inhibitors, such as GSK8814 and AZ13824374, have also been discovered. Thus, in this review, we focus on summarizing the structural features and biological functions of ATAD2 from an epigenetic modulator to a cancer therapeutic target, and further discuss the existing small-molecule inhibitors targeting ATAD2 to improve potential cancer therapy. Together, these inspiring findings would shed new light on ATAD2 as a promising druggable target in cancer and provide a clue on the development of candidate anticancer drugs.

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“…Further studies led to identification of two less potent ATAD2 inhibitors 650 [435] and 651 [436] with the same binding mode also bearing the gem ‐difluorocyclohexyl moiety (Figure 58).…”

Section: Biologically Active Derivatives Of Fluorinated Cycloalkyl Bu...mentioning

confidence: 99%

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

et al. 2022

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The review covers various aspects of fluorinated cycloalkyl (C3−C7) building blocks for drug discovery, including their synthesis, key physicochemical properties, and biological and medicinal applications of their derivatives. The discussed synthetic methods include classical nucleophilic fluorinations of various substrates, the addition of fluorine and another heteroatom to double bonds, cycloadditions and other transformations of fluorine‐containing substrates, as well as some newer reactions like fluorination of non‐activated and remotely activated C−H bonds, decarboxylative and deborylative fluorinations, etc. The known data on the effect of introducing the fluorinated cycloalkyl groups on the compound's key in vitro parameters (such as acidity/basicity, lipophilicity, conformational behavior, and short contact capabilities) are surveyed. Finally, applications of fluorinated cycloalkyl building block derivatives in the design of biologically active compounds (including marketed drugs Maraviroc, Ivosidenib, and Sitafloxacin) are covered, with a focus on the fluorination impact.

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Hitting a Moving Target: Simulation and Crystallography Study of ATAD2 Bromodomain Blockers

Cited by 9 publications

References 33 publications

Identification of a BAZ2A Bromodomain Hit Compound by Fragment Joining

Identification of a BAZ2A Bromodomain Hit Compound by Fragment Joining

ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

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