3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine

Uses

SEN177 is an orally effect glutamine cyclase (QC) inhibitor. The Ki of SEN177 for human glutamine cyclase (hQC) is 20 nM, and the IC50 is 13 nM. SEN177 interferes with the interaction between CD47 and SIRRPα, and has anti-tumor activity. SEN177 reduces aggregation and apoptosis caused by HTT mutation in Huntington model, and can be used in the study of neurodegenerative diseases[1][2][3].

Definition

ChEBI: SEN177 is a member of bipyridines.

Biological Activity

SEN177 is a Glutaminyl cyclase (QPCT) inhibitor. Glutaminyl cyclase modifies N-terminal glutamine or glutamate residues to N-terminal 5-oxoproline or pyroglutamate (named QPCT). QPCT inhibits mutant huntingtin from forming aggregates, but also reduces aggregation of other aggregate-prone proteins containing polyQ or polyA repeats. SEN177 caused dose-dependent decreases in HTT aggregation by a mechanism th at requires QPCT inhibition. SEN177 had in vitro activity against polyglutamine toxicity and was able to reduce aggregates in mammalian cells, primary neurons and in a Drosophila model.

in vivo

storage

Store at -20°C

References

[1] Cecilia Pozzi, et al. The structure of the human glutaminyl cyclase-SEN177 complex indicates routes for developing new potent inhibitors as possible agents for the treatment of neurological disorders. J Biol Inorg Chem. 2018 Dec;23(8):1219-1226. DOI:10.1007/s00775-018-1605-1
[2] Baumann N, et al. Enhancement of epidermal growth factor receptor antibody tumor immunotherapy by glutaminyl cyclase inhibition to interfere with CD47/signal regulatory protein alpha interactions. Cancer Sci. 2021 Aug;112(8):3029-3040. DOI:10.1111/cas.14999
[3] Maria Jimenez-Sanchez, et al. siRNA screen identifies QPCT as a druggable target for Huntington's disease. Nat Chem Biol. 2015 May;11(5):347-354. DOI:10.1038/nchembio.1790