UNC0642 is a potent and selective G9a/GLP inhibitor, with an IC50 of less than 2.5 nM.
UNC0642 displays high in vitro and cellular potency, low cell toxicity, and excellent selectivity. UNC0642 is competitive with the peptide substrate and non-competitive with the cofactor SAM. The Ki of UNC0642 is determined to be 3.7±1 nM. UNC0642 displays high in vitro potency for GLP (IC50< 2.5 nM), similar to G9a. UNC0642 is more than 300-fold selective for G9a and GLP over a broad range of kinases, GPCRs, transporters, and ion channels. UNC0642 exhibits high potency at reducing the H3K9me2 mark, low cell toxicity, and good separation of functional potency and cell toxicity in a number of cell lines. It reduces clonogenicity in PANC-1 cells, a pancreatic carcinoma cell line[1].
A single intraperitoneal (IP) injection (5 mg/kg) of UNC0642results in a plasma Cmax (maximum concentration) of 947 ng/mL and an AUC (area under the curve) of 1265 hr*ng/mL[1].
References:
[1]. Liu F, et al. Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J Med Chem. 2013 Nov 14;56(21):8931-8942.
[2]. Wang L, et al. Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway. Cell Death Dis. 2018 Jan 26;9(2):129