1G244 | DPP8/9 inhibitor

1G244 (847928-32-9) is a potent and selective inhibitor of the prolyl dipeptidases DPP8 (IC₅₀ = 14 nM) and DPP9 (IC₅₀ = 53 nM).^1,2  It does not inhibit DPP2, DPP4 or fibroblast activation protein (FAP) at 100 µM.^1,2 1G244 is a slow binding competitive inhibitor of DPP8 but a competitive and reversible inhibitor of DPP9.²  Inhibition of DPP8/9 by 1G244 has been shown to cause pro-caspase-1-dependent pyroptosis in macrophages and monocytes.³ 1G244 also induced cell death in DPP8/9 knockout cells at higher concentration indicating there may be some off-target effects.³ 1G244 blocks adipogenesis in preadipocyte 3T3-L1 and 3T3-F422A cells.⁴  DPP8/9 inhibition attenuates PPARg2 induction during preadipocyte differentiation.⁴ Because of its inhibitory effects on pro-inflammatory macrophages, 1G244 inhibition of DPP8/9 has been examined as a potential therapy for reducing atherosclerosis and/or in the prevention of plaque rupture.^5,6 Cell permeable.

References/Citations:

1. Jiaang et al. (2005), Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8; Bioorg.Med.Chem.Lett.15 687
2. Wu et al. (2009), Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor; Biochem.Pharmacol. 78 203
3. Okondo et al. (2017), DPP8/9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis; Nat.Chem.Biol. 13 46
4. Han et al. (2015), Inhibition of dipeptidyl peptidase 8/9 impairs preadipocyte differentiation; Sci.Rep. 5 12348
5. Matheeussen et al. (2013), Dipeptidyl peptidases in atherosclerosis: expression and role in macrophage differentiation, activation and apoptosis; Basic Res.Cardiol. 108 350
6. Waumans et al. (2016), The Dipeptidyl Peptidases 4,8, and 9 in Mouse Monocytes and Macrophages: DPP8/9 Inhibition Attenuates M1 Macrophage Activation in Mice; Inflammation 39 413