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A novel chemical attack on Notch-mediated transcription by targeting the NACK ATPase

Notch activation complex kinase (NACK) is a component of the Notch transcriptional machinery critical for the Notch-mediated tumorigenesis. However, the mechanism through which NACK regulates Notch-mediated transcription is not well understood. Here, we demonstrate that NACK binds and hydrolyzes ATP...

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Autores principales: Diluvio, Giulia, Kelley, Tanya T., Lahiry, Mohini, Alvarez-Trotta, Annamil, Kolb, Ellen M., Shersher, Elena, Astudillo, Luisana, Kovall, Rhett A., Schürer, Stephan C., Capobianco, Anthony J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015116/
https://www.ncbi.nlm.nih.gov/pubmed/36938545
http://dx.doi.org/10.1016/j.omto.2023.02.008
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author Diluvio, Giulia
Kelley, Tanya T.
Lahiry, Mohini
Alvarez-Trotta, Annamil
Kolb, Ellen M.
Shersher, Elena
Astudillo, Luisana
Kovall, Rhett A.
Schürer, Stephan C.
Capobianco, Anthony J.
author_facet Diluvio, Giulia
Kelley, Tanya T.
Lahiry, Mohini
Alvarez-Trotta, Annamil
Kolb, Ellen M.
Shersher, Elena
Astudillo, Luisana
Kovall, Rhett A.
Schürer, Stephan C.
Capobianco, Anthony J.
author_sort Diluvio, Giulia
collection PubMed
description Notch activation complex kinase (NACK) is a component of the Notch transcriptional machinery critical for the Notch-mediated tumorigenesis. However, the mechanism through which NACK regulates Notch-mediated transcription is not well understood. Here, we demonstrate that NACK binds and hydrolyzes ATP and that only ATP-bound NACK can bind to the Notch ternary complex (NTC). Considering this, we sought to identify inhibitors of this ATP-dependent function and, using computational pipelines, discovered the first small-molecule inhibitor of NACK, Z271-0326, that directly blocks the activity of Notch-mediated transcription and shows potent antineoplastic activity in PDX mouse models. In conclusion, we have discovered the first inhibitor that holds promise for the efficacious treatment of Notch-driven cancers by blocking the Notch activity downstream of the NTC.
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spelling pubmed-100151162023-03-16 A novel chemical attack on Notch-mediated transcription by targeting the NACK ATPase Diluvio, Giulia Kelley, Tanya T. Lahiry, Mohini Alvarez-Trotta, Annamil Kolb, Ellen M. Shersher, Elena Astudillo, Luisana Kovall, Rhett A. Schürer, Stephan C. Capobianco, Anthony J. Mol Ther Oncolytics Original Article Notch activation complex kinase (NACK) is a component of the Notch transcriptional machinery critical for the Notch-mediated tumorigenesis. However, the mechanism through which NACK regulates Notch-mediated transcription is not well understood. Here, we demonstrate that NACK binds and hydrolyzes ATP and that only ATP-bound NACK can bind to the Notch ternary complex (NTC). Considering this, we sought to identify inhibitors of this ATP-dependent function and, using computational pipelines, discovered the first small-molecule inhibitor of NACK, Z271-0326, that directly blocks the activity of Notch-mediated transcription and shows potent antineoplastic activity in PDX mouse models. In conclusion, we have discovered the first inhibitor that holds promise for the efficacious treatment of Notch-driven cancers by blocking the Notch activity downstream of the NTC. American Society of Gene & Cell Therapy 2023-02-22 /pmc/articles/PMC10015116/ /pubmed/36938545 http://dx.doi.org/10.1016/j.omto.2023.02.008 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Diluvio, Giulia
Kelley, Tanya T.
Lahiry, Mohini
Alvarez-Trotta, Annamil
Kolb, Ellen M.
Shersher, Elena
Astudillo, Luisana
Kovall, Rhett A.
Schürer, Stephan C.
Capobianco, Anthony J.
A novel chemical attack on Notch-mediated transcription by targeting the NACK ATPase
title A novel chemical attack on Notch-mediated transcription by targeting the NACK ATPase
title_full A novel chemical attack on Notch-mediated transcription by targeting the NACK ATPase
title_fullStr A novel chemical attack on Notch-mediated transcription by targeting the NACK ATPase
title_full_unstemmed A novel chemical attack on Notch-mediated transcription by targeting the NACK ATPase
title_short A novel chemical attack on Notch-mediated transcription by targeting the NACK ATPase
title_sort novel chemical attack on notch-mediated transcription by targeting the nack atpase
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015116/
https://www.ncbi.nlm.nih.gov/pubmed/36938545
http://dx.doi.org/10.1016/j.omto.2023.02.008
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