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 Notchmediated 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 Notchdriven cancers by blocking the Notch activity downstream of the NTC.

Automated summary

In this study, the first small-molecule inhibitor of NACK, Z271-0326, was discovered, which directly blocks Notch-mediated transcription and exhibits potent antineoplastic activity in PDX mouse models.