MS177

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 arrest In Vitro MS177 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 Vivo MS177 (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:Solid IC50& Target:EZH2

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