Giulia Diluvio, Tanya T Kelley, Mohini Lahiry, Annamil Alvarez-Trotta, Ellen M Kolb, Elena Shersher, Luisana Astudillo, Rhett A Kovall, Stephan C Schürer, Anthony J Capobianco
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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 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.
期刊介绍：
Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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