Description
MS177 is an effective and fast-acting EZH2 degrader. MS177 is a PROTAC that consists of a CRBN ligand, linker, and a potent enzymatic EZH2 inhibitor C24 (C24 IC 50 ): 12 nM). MS177 effectively depletes both canonical EZH2–PRC2 and noncanonical EZH2–cMyc complexes. MS177 induces leukaemia cell growth inhibition, apoptosis and cell cycle progression arrestIn VitroMS177 inhibits the enzymatic activities of EZH2-PRC2 (IC 50 : 7 nM). MS177 (5 µM, 24 h) decreases H3K27me3 and increases H3K27activity in HeLa cells. MS177 (0.1-5 µM, 16 h) effectively degrades cellular EZH2-PRC2 and suppresses global H3K27me3 in EOL-1 cells. MS177 (0.1-5 µM, 16 h) induces Myc degradation in EOL-1 and MV4 cells. MS177 (4 days) shows antiproliferation effects in a panel of MLL-r leukaemia cells and samples from patients with AML, with IC 50 s below 2 µM. MS177 (0.5-2.5 µM, 24 h) decreases colony-forming capabilities in MV4;11 cells. MS177 (0.5-2.5 µM, 24 h) slows cell cycle progression and induces MOLM-13 cell apoptosis. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Viability AssayCell Line: AML cell line: MV4;11, MOML-13, RS4;11, KOPN-8 THP-1, EOL-1 (MLL-r cells) Control cell line: K562 (CML cells) Patient sample: AML cells Concentration: 0-100 µM approximately Incubation Time: 4 days Result: Inhibited cell proliferation with IC 50 s of 0.1-0.57 µM for MLL-r cells, 0.09-1.35 µM for Patient sample, >100 µM for K562 cell. Western Blot AnalysisCell Line: EOL-1 cell Concentration: 0.1, 0.5, 1, 2.5, 5 µM Incubation Time: 16 h Result: Depleted EZH2, EED and SUZ12 in a concentration-dependent manner and suppressed global H3K27me3.In VivoMS177 (100 mg/kg, i.p., BID for 6 days) represses tumor growth in PDX animal model of MLL-r AML, and in subcutaneously xenografted MLL-r leukaemia models. MS177 (50 mg/kg, i.p.) achieves intraplasma concentrations about 1 µM in male Swiss Albino mice. MS177 (100 mg/kg, i.p., BID for 6 days per week; and 200 mg/ kg, i.p. BID 3 days per week) is well tolerated and lacks apparent toxicity in mice. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: PDX animal model of MLL-r AML Dosage: 100 mg/kg Administration: Intraperitoneal injection (i.p.), BID for 6 days. Result: Inhibited tumor growth and prolonged survival.Form:SolidIC50& Target:EZH2