scholarly journals Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

2014 ◽  
Vol 13 (6) ◽  
pp. 1457-1467 ◽  
Author(s):  
Dipanjan Basu ◽  
Robert Lettan ◽  
Krishnan Damodaran ◽  
Susan Strellec ◽  
Miguel Reyes-Mugica ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Small Molecule ◽  
Mechanism Of Action ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Identification Mechanism

scholarly journals A Novel Chemical Attack on Notch-mediated transcription by targeting the NACK ATPase

2021 ◽  
Author(s):  
G. Diluvio ◽  
T. T. Kelley ◽  
M. Lahiry ◽  
A. Alvarez Trotta ◽  
E. M. Kolb ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Mouse Models ◽  
Small Molecule ◽  
Ternary Complex ◽  
Small Molecule Inhibitor ◽  
Chemical Attack ◽  
Dependent Function ◽  
Molecule Inhibitor ◽  
Efficacious Treatment ◽  
Notch Activation

Abstract Notch Activation Complex Kinase, NACK, is a component of the Notch transcriptional machinery critical to Notch-mediated tumorigenesis. However, the mechanism by which NACK regulates the Notch-mediated transcription is not well understood. Here we demonstrate that NACK binds and hydrolyses ATP and that only ATP-bound NACK is able to 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 antitumor activity in PDX mouse models. In conclusion, we have discovered the first inhibitor that holds promise for efficacious treatment of Notch-driven cancers by blocking the Notch downstream NTC activity.

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