Remodelin Is a Cryptic Assay Interference Chemotype That Does Not Inhibit NAT10-Dependent Cytidine Acetylation

Shrimp, Jonathan J.H.; Jing, Yihang; Gamage, Supuni Thalalla; Nelson, Kathryn K.M.; Han, James Y.; Bryson, Keri K.M.; Montgomery, David D.C.; Thomas, Justin M.; Nance, Kellie D.; Sharma, Sunny; Fox, Stephen B.; Andressen, Thorkell; Sinclair, Wilson W.R.; Wu, Hong; Allali-Hassani, Abdellah; Vedadi, Masoud; Lafontaine, Denis L. J.; Dahlin, Jayme J.L.; Marmorstein, Ronen; Walters, Michael A.; Meier, Jordan

doi:10.1021/acsmedchemlett.0c00193

Cited by 21 publications

(13 citation statements)

References 33 publications

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“…In line with this prediction, Larrieu et al reported decreased acetyltransferase activity upon treatment with Remodelin in an in vitro study conducted in Hutchinson-Gilford progeria syndrome (HGPS) 7 . A biophysical study by Shrimp et al 2020 showed that Remodelin does not inhibit NAT10 dependent cytidine acetylation and could interact with multiple protein targets in the cell 21 . Contrary to this assertion, our predictive study is in line with Larrieu et al showing Remodelin binds to the acetyl-CoA binding site, and could affect acetylation activity by preventing the proper binding of acetyl-CoA which is a substrate to RNA and protein acetylation 7 .…”

Section: Discussionmentioning

confidence: 99%

Structural insights of human N-acetyltransferase 10 and identification of its potential novel inhibitors

Dalhat

Altayb

Khan

et al. 2021

Sci Rep

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N-acetyltransferase 10 (NAT10), is an acetyltransferase that regulates RNA stability and translation processes. Association of NAT10 with several diseases including cancer, makes it a promising therapeutic target. Remodelin is the only known NAT10 inhibitor, but the structural information related to its binding with NAT10 is still obscure. Here, we predicted the human NAT10 structure using homology modeling that was not available previously and used human NAT10 to identify the novel binding site(s) of Remodelin. The alignment of the modeled human NAT10 showed 24% identity and 37% positivity with crystal structure of tRNA (Met) cytidine acetyltransferase. Molecular docking showed binding of Remodelin with NAT10 in acetyl-CoA binding pocket. Additionally, we screened a library of FDA-approved drugs for the identification of novel inhibitors of NAT10 activity. Binding score showed that four drugs namely, Fosaprepitant (− 11.709), Leucal (− 10.46), Fludarabine (− 10.347) and Dantrolene (− 9.875) bind to NAT10 and have better binding capability when compared with Acetyl-CoA (− 5.691) and Remodelin (− 5.3). Acetyl-CoA, Remodelin, and others exhibit hits for hydrophobic, hydrophilic and hydrogen interactions. Interestingly, Remodelin and others interact with the amino acid residues ILE629, GLY639, GLY641, LEU719, and PHE722 in the Acetyl-CoA binding pocket of NAT10 similar to Acetyl-CoA. Our findings revealed that Fosaprepitant, Leucal, Fludarabine, and Dantrolene are promising molecules that can be tested and developed as potential inhibitors of NAT10 acetyltransferase activity.

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Section: Discussionmentioning

confidence: 99%

Structural insights of human N-acetyltransferase 10 and identification of its potential novel inhibitors

Dalhat

Altayb

Khan

et al. 2021

Sci Rep

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“…Studies have reported Remodelin as a potential cancer drug therapeutic agent, 43,44 but its structural NAT10 binding information is not yet available. 45,46 After sufficient overexpression of NAT10 in mouse hearts, Remodelin failed to show its preventive effects after TAC challenge, indicating that Remodelin acts by inhibiting NAT10 (Figure S10F). Therefore, our findings suggest that Remodelin holds potential as a viable therapeutic intervention for the prevention and treatment of cardiac remodeling.…”

Section: Discussionmentioning

confidence: 99%

NAT10 Is Involved in Cardiac Remodeling Through ac4C-Mediated Transcriptomic Regulation

Shi,

Yang,

Zhang

et al. 2023

Circulation Research

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Background: Heart failure, characterized by cardiac remodeling, is associated with abnormal epigenetic processes and aberrant gene expression. Here, we aimed to elucidate the effects and mechanisms of NAT10 (N-acetyltransferase 10)-mediated N4-acetylcytidine (ac4C) acetylation during cardiac remodeling. Methods: NAT10 and ac4C expression were detected in both human and mouse subjects with cardiac remodeling through multiple assays. Subsequently, acetylated RNA immunoprecipitation and sequencing, thiol (SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq), and ribosome sequencing (Ribo-seq) were employed to elucidate the role of ac4C-modified posttranscriptional regulation in cardiac remodeling. Additionally, functional experiments involving the overexpression or knockdown of NAT10 were conducted in mice models challenged with Ang II (angiotensin II) and transverse aortic constriction. Results: NAT10 expression and RNA ac4C levels were increased in in vitro and in vivo cardiac remodeling models, as well as in patients with cardiac hypertrophy. Silencing and inhibiting NAT10 attenuated Ang II-induced cardiomyocyte hypertrophy and cardiofibroblast activation. Next-generation sequencing revealed ac4C changes in both mice and humans with cardiac hypertrophy were associated with changes in global mRNA abundance, stability, and translation efficiency. Mechanistically, NAT10 could enhance the stability and translation efficiency of CD47 and ROCK2 transcripts by upregulating their mRNA ac4C modification, thereby resulting in an increase in their protein expression during cardiac remodeling. Furthermore, the administration of Remodelin, a NAT10 inhibitor, has been shown to prevent cardiac functional impairments in mice subjected to transverse aortic constriction by suppressing cardiac fibrosis, hypertrophy, and inflammatory responses, while also regulating the expression levels of CD47 and ROCK2. Conclusions: Therefore, our data suggest that modulating epitranscriptomic processes, such as ac4C acetylation through NAT10, may be a promising therapeutic target against cardiac remodeling.

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“…Finally, the effort for pharmaceutically targeting NAT10‐ac4C should not be abandoned; especially there are already some highly specific NAT10 binding molecules available. Although their efficacy for acetyltransferase activity inhibition seems to be weak 7,8 . Learn from the success of small molecular inhibitor development for m6A modification, 9 investigators are expected to develop potent molecule for NAT10‐ac4C inhibition in a foreseeable future.…”

Section: Figurementioning

confidence: 99%

“…Although their efficacy for acetyltransferase activity inhibition seems to be weak. 7,8 Learn from the success of small molecular inhibitor development for m6A modification, 9 investigators are expected to develop potent molecule for NAT10-ac4C inhibition in a foreseeable future.…”

mentioning

confidence: 99%

mRNA cytidine N4‐acetylation by NAT10 modulates lipid utilization in breast cancer

Wong

2022

Clinical and Translational Dis

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Remodelin Is a Cryptic Assay Interference Chemotype That Does Not Inhibit NAT10-Dependent Cytidine Acetylation

Cited by 21 publications

References 33 publications

Structural insights of human N-acetyltransferase 10 and identification of its potential novel inhibitors

Structural insights of human N-acetyltransferase 10 and identification of its potential novel inhibitors

NAT10 Is Involved in Cardiac Remodeling Through ac4C-Mediated Transcriptomic Regulation

mRNA cytidine N4‐acetylation by NAT10 modulates lipid utilization in breast cancer

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