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 IC50): 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[1].
MS177 inhibits the enzymatic activities of EZH2-PRC2 (IC50: 7 nM)[1].
MS177 (5 μM, 24 h) decreases H3K27me3 and increases H3K27activity in HeLa cells[1].
MS177 (0.1-5 μM, 16 h) effectively degrades cellular EZH2-PRC2 and suppresses global H3K27me3 in EOL-1 cells[1].
MS177 (0.1-5 μM, 16 h) induces Myc degradation in EOL-1 and MV4 cells[1].
MS177 (4 days) shows antiproliferation effects in a panel of MLL-r leukaemia cells and samples from patients with AML, with IC50s below 2 μM[1].
MS177 (0.5-2.5 μM, 24 h) decreases colony-forming capabilities in MV4;11 cells[1].
MS177 (0.5-2.5 μM, 24 h) slows cell cycle progression and induces MOLM-13 cell apoptosis[1].
Cell Viability Assay[1]
| Cell 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 IC50s 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 Analysis[1]
| Cell 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. |
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[1].
MS177 (50 mg/kg, i.p.) achieves intraplasma concentrations about 1 μM in male Swiss Albino mice[1].
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[1].
| Animal Model: | PDX animal model of MLL-r AML[1] |
| Dosage: | 100 mg/kg |
| Administration: | Intraperitoneal injection (i.p.), BID for 6 days. |
| Result: | Inhibited tumor growth and prolonged survival. |