Tideglusib inhibits NatA via a prodrug mechanism by forming a bisubstrate analog in situ

ABSTRACT: N-terminal acetyltransferase A (NatA) is responsible for 40-57% of the eukaryotic N-terminal acetylation. NatA-mediated N-terminal acetylation is involved in various cellular processes, including protein folding, stability, localization, signaling, and gene regulation. However, no small molecular inhibitor for NatA has been reported to date. Here, we report the identification of two validated compounds TDZD-8 and CX-6258 through screening of ~ 700 in-house compounds. Kinetic studies indicate that tideglusib functions as reversible allosteric inhibitors of NatA. Yeast growth inhibition and proteomics studies further confirm the inhibition of yNatA by tideglusib (YD3139). Tideglusib represents a bona fide yNatA inhibitor, which would serve as a lead compound for further optimization to improve its selectivity. Additionally, this is the first disclosure of yNatA as a new molecular target of tideglusib, a promiscuous GSK-3 inhibitor currently in clinical trials.

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Rong Huang 

PROVIDER: PXD070476 | JPOST Repository | Sun Nov 08 00:00:00 GMT 2026

REPOSITORIES: jPOST