DG-172 (hydrochloride)

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Background

DG-172 (hydrochloride) is an orally available inverse agonist of PPARβ/δ with IC50 value of 27 nM [1]. Peroxisome proliferator-activated receptors (PPARs) are a member of the class II subset of nuclear receptors. The three PPAR subtypes (PPARα, PPARβ/δ, and PPARγ) regulate their target genes through binding to specific DNA elements (PPREs) as obligatory heterodimers with the retinoid X receptor. PPRE-bound PPARβ/δ complexes have functions in both transcriptional repression and transcriptional activation [1]. DG-172 is a novel PPARβ/δ-selective ligand and an orally available PPARβ/δ inverse agonist with IC50 value of 27 nM. In a cell-based assay, DG-172 efficiently antagonized ligand activation of PPARβ/δ. In C2C12 mouse myoblasts, DG-172 inhibited the expression of PPARβ/δ target gene Angptl4 with IC50 value of 9.5 nM. In WPMY-1 human myofibroblasts, DG-172 induced an enhanced recruitment of HDAC3 to the ANGPTL4 gene [1]. DG172 strongly increased GM-CSF-induced differentiation of primary BMCs into two specific populations, mature and immature dendritic cells (DCs) [2]. DG172 strongly inhibited the serum- and transforming growth factor b (TGFb)-induced invasion of MDA-MB-231 human breast cancer cells into a three-dimensional matrigel matrix [3].

[1]. Lieber S, Scheer F, Meissner W, et al. (Z)-2-(2-bromophenyl)-3-{[4-(1-methyl-piperazine)amino]phenyl}acrylonitrile (DG172): an orally bioavailable PPARβ/δ-selective ligand with inverse agonistic properties. J Med Chem. 2012 Mar 22;55(6):2858-68.
[2]. Lieber S, Scheer F, Finkernagel F, et al. The inverse agonist DG172 triggers a PPARβ/δ-independent myeloid lineage shift and promotes GM-CSF/IL-4-induced dendritic cell differentiation. Mol Pharmacol. 2015 Feb;87(2):162-73.
[3]. Adhikary T, Brandt DT, Kaddatz K, et al. Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion. Oncogene. 2013 Oct 31;32(44):5241-52.