MS1943

一种PROTAC（蛋白降解靶向嵌合体），能够诱导EZH2降解。它抑制EZH2的活性，IC50为120nM，并且对EZH2的选择性高于EZH1以及45种激酶（在10µM浓度下）。在MDA-MB-468三阴性乳腺癌细胞中，该化合物在4µM浓度下诱导EZH2降解，降低H3K27me3水平，并激活未折叠蛋白反应通路。此外，它在体外抑制MDA-MB-468细胞生长（GI50=2.2µM），并在MDA-MB-468小鼠异种移植模型中，以每周三次、每次1或10mg/kg的剂量给药时，显著减少肿瘤体积。A PROTAC that drives EZH2 degradation; inhibits EZH2 (IC50 = 120 nM) and is selective for EZH2 over EZH1, as well as a panel of 45 kinases at 10 µM; induces EZH2 degradation and reduces H3K27me3, as well as induces activation of the unfolded protein response pathway in MDA-MB-468 TNBC cells at 4 µM; inhibits the growth of MDA-MB-468 cells in vitro (GI50 = 2.2 µM); reduces tumor volume in an MDA-MB-468 mouse xenograft model at 50 mg/kg.分子式C42H54N8O3分子量718.9CC(C)N1N=CC2=C(C=C(C3=CC=C(N4CCN(CC4)CCNC(CC56CC7CC(C6)CC(C5)C7)=O)N=C3)C=C21)C(NCC8=C(C)C=C(C)NC8=O)=O