Development of BRD4 inhibitors as anti-inflammatory agents and antidotes for arsenicals

Yatchang, Marina Fosso; Mathew, Biji; Srivastavá, R. C.; Khan, Jasim; Muzaffar, Suhail; Zhang, Sixue; Wu, Mousheng; Zhai, Ling; Ruiz, Pedro; Agarwal, Anupam; Bostwick, J. Robert; Suto, Mark J.; Athar, Mohammad; Augelli‐Szafran, Corinne E.

doi:10.1016/j.bmcl.2022.128696

Cited by 4 publications

(3 citation statements)

References 28 publications

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“…Interestingly, ongoing work has identified a role for bromodomain-containing protein 4 (BRD4) inhibition in mitigating the effects of arsenical-induced injury and novel small molecule therapeutics targeting BRD4 are currently being developed (Yatchang et al, 2022). While it is believed the primary mechanism of action of BRD4 inhibition is the attenuation of inflammation, a recent study suggests that it also affects metabolism (Barrow et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Cutaneous Arsenical Exposure Induces Distinct Metabolic Transcriptional Alterations of Kidney Cells

Moore,

Boitet,

Chandrashekar

et al. 2023

J Pharmacol Exp Ther

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Arsenicals are deadly chemical warfare agents which primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenical exposure is also known to cause acute kidney injury, a condition that contributes to arsenical-associated death due to the necessity of the kidney in maintaining whole-body fluid homeostasis. Because of the global health risk that arsenicals pose, a nuanced understanding of how arsenical exposure can lead to kidney injury is needed. We utilized a non-targeted transcriptional approach to evaluate the effects of cutaneous exposure to phenylarsine oxide, a common arsenical, in a murine model.Here we identified an upregulation of metabolic pathways such as fatty acid oxidation, fatty acid biosynthesis, and PPAR-𝛼 signaling in proximal tubule epithelial cell and endothelial cell clusters. We also revealed highly upregulated genes such as Zbtb16, Cyp4a14, and Pdk4, which are involved in metabolism and metabolic switching and may serve as future therapeutic targets. The ability of arsenicals to inhibit enzymes such as pyruvate dehydrogenase have been previously described in vitro. This along with our own data lead us to conclude that arsenicalinduced acute kidney injury may be due to a metabolic impairment in proximal tubule and endothelial cells, and that ameliorating these metabolic effects may lead to the development of life-saving therapies.

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Section: Discussionmentioning

confidence: 99%

Cutaneous Arsenical Exposure Induces Distinct Metabolic Transcriptional Alterations of Kidney Cells

Moore,

Boitet,

Chandrashekar

et al. 2023

J Pharmacol Exp Ther

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“…Nucleophilic substitution at the sp 3 carbon atom can in principle compete with the SuFEx reaction; [81] still, there are many successful examples of such transformations where the SO 2 F group remains intact (Scheme 6). In particular, S N 2 reactions of primary alkyl halides (mostly bromides) bearing a sulfonyl fluoride fragment with azide,, [82,83] secondary amines, [33,35,[84][85][86][87][88] N-silylated uracil, [58] phenolates, [89] PPh 3 , [90] P(OEt) 3 , [91] and imidazole [92] were reported. The SO 2 F moiety survived transformation of benzylic alcohols into the corresponding bromides upon action of anhydrous 30 % HBr in AcOH [57,58] or under Appel reaction conditions (CBr 4 -PPh 3 ).…”

Section: R E V I E W T H E C H E M I C a L R E C O R Dmentioning

confidence: 99%

Chemoselective Reactions of Functionalized Sulfonyl Halides

Liashuk,

Andriashvili,

Tolmachev

et al. 2023

The Chemical Record

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Chemoselective transformations of functionalized sulfonyl fluorides and chlorides are surveyed comprehensively. It is shown that sulfonyl fluorides provide an excellent selectivity control in their reactions. Thus, numerous conditions are tolerated by the SO2F group – from amide and ester formation to directed ortho‐lithiation and transition‐metal‐catalyzed cross‐couplings. Meanwhile, sulfur (VI) fluoride exchange (SuFEx) is also compatible with numerous functional groups, thus confirming its title of “another click reaction”. On the contrary, with a few exceptions, most transformations of functionalized sulfonyl chlorides typically occur at the SO2Cl moiety.

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“…Other important molecules include the bromodomain and extra terminal (BET)-containing protein family. BET proteins act as an epigenetic reader that is a key positive regulator of NF-κB and transforming growth factor TGF-β dependent pro-inflammatory gene expression [ 87 ], acting as a critical co-activator in the process of cardiomyocyte hypertrophy [ 88 ]. Bromodomain-containing protein 4 (BRD4) binds acetyl-lysine via bromodomains and co-activates transcription, forming complexes that signal to RNA polymerase II and react directly with NF-κB through acetylated Lys310 of the p65 subunit.…”

Section: The Role Of Epigenetics In Inflammationmentioning

confidence: 99%

The Role of Selected Epigenetic Pathways in Cardiovascular Diseases as a Potential Therapeutic Target

Wołowiec,

Grześk

et al. 2023

IJMS

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Epigenetics is a rapidly developing science that has gained a lot of interest in recent years due to the correlation between characteristic epigenetic marks and cardiovascular diseases (CVDs). Epigenetic modifications contribute to a change in gene expression while maintaining the DNA sequence. The analysis of these modifications provides a thorough insight into the cardiovascular system from its development to its further functioning. Epigenetics is strongly influenced by environmental factors, including known cardiovascular risk factors such as smoking, obesity, and low physical activity. Similarly, conditions affecting the local microenvironment of cells, such as chronic inflammation, worsen the prognosis in cardiovascular diseases and additionally induce further epigenetic modifications leading to the consolidation of unfavorable cardiovascular changes. A deeper understanding of epigenetics may provide an answer to the continuing strong clinical impact of cardiovascular diseases by improving diagnostic capabilities, personalized medical approaches and the development of targeted therapeutic interventions. The aim of the study was to present selected epigenetic pathways, their significance in cardiovascular diseases, and their potential as a therapeutic target in specific medical conditions.

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Development of BRD4 inhibitors as anti-inflammatory agents and antidotes for arsenicals

Cited by 4 publications

References 28 publications

Cutaneous Arsenical Exposure Induces Distinct Metabolic Transcriptional Alterations of Kidney Cells

Cutaneous Arsenical Exposure Induces Distinct Metabolic Transcriptional Alterations of Kidney Cells

Chemoselective Reactions of Functionalized Sulfonyl Halides

The Role of Selected Epigenetic Pathways in Cardiovascular Diseases as a Potential Therapeutic Target

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