Notch activation complex kinase (NACK) (NACK)

Notch activation complex kinase (NACK), encoded by the PRAG1 gene, is an atypical kinase or pseudokinase that serves as a critical co-activator within the Notch1 transcriptional complex [1.1.1, 1.5.4]. It is recruited to the Notch Ternary Complex (NTC)—consisting of the Notch intracellular domain (NICD), CSL, and Mastermind-like (MAML)—following the p300-mediated acetylation of MAML [1.5.1, 1.5.2]. NACK acts as a scaffold to facilitate the recruitment of RNA polymerase II and the Integrator complex to Notch target promoters, thereby driving the expression of genes essential for cell proliferation and survival [1.5.1]. In various malignancies, including esophageal and pancreatic adenocarcinomas, NACK is frequently overexpressed and participates in a feed-forward loop with Notch signaling to promote tumorigenesis and maintain cancer stem cell populations [1.1.1, 1.3.1]. Unlike traditional gamma-secretase inhibitors (GSIs) that cause severe intestinal toxicity, small-molecule inhibitors targeting NACK (such as Z271-0326) or the Notch1-specific complex (such as NADI-351) have shown the ability to suppress tumor growth without inducing goblet cell metaplasia in preclinical models [1.1.5, 1.5.2]. Consequently, NACK represents a promising therapeutic target for Notch-dependent cancers, offering a more selective approach to pathway inhibition [1.5.3].

Other names

PRAG1SGK223PRAGMINPEAK2PEAK1-related kinase-activating pseudokinase 1

Disruption of the Notch1 transcriptional complex assembly, inhibition of NACK ATPase activity, and prevention of RNA polymerase II recruitment to Notch target promoters.