MS177

• CAT Number: I042627
• CAS Number: 2225938-86-1
• Molecular Formula: C48H55N11O8
• Molecular Weight: 914.02
• Purity: ≥95%
• Synonyms: N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-6-[6-[4-[2-[3-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]propanoylamino]ethyl]piperazin-1-yl]pyridin-3-yl]-1-propan-2-ylindazole-4-carboxamide
• InChI: InChI=1S/C48H55N11O8/c1-28(2)59-39-24-32(23-34(36(39)27-53-59)44(62)52-26-35-29(3)22-30(4)54-45(35)63)31-8-10-40(51-25-31)57-18-16-56(17-19-57)15-13-50-41(60)12-20-67-21-14-49-37-7-5-6-33-43(37)48(66)58(47(33)65)38-9-11-42(61)55-46(38)64/h5-8,10,22-25,27-28,38,49H,9,11-21,26H2,1-4H3,(H,50,60)(H,52,62)(H,54,63)(H,55,61,64)
• InChIKey: LRMNSTSNSCJHGZ-UHFFFAOYSA-N
• SMILES: CC1=CC(=C(C(=O)N1)CNC(=O)C2=C3C=NN(C3=CC(=C2)C4=CN=C(C=C4)N5CCN(CC5)CCNC(=O)CCOCCNC6=CC=CC7=C6C(=O)N(C7=O)C8CCC(=O)NC8=O)C(C)C)C

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].
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].

Reference

[1]. Wang J, et al. EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis. Nat Cell Biol. 2022 Mar;24(3):384-399.
 [Content Brief]