治疗伊马替尼耐药的慢性粒细胞白血病的新型多肽SP2及其作用机制

A novel peptide and its mechanism overcoming imatinib-resistance chronic myeloid leukemia

摘要: 载脂蛋白E模拟多肽COG133具有拮抗SET蛋白和提高细胞中蛋白磷酸酶2A(PP2A)活性，可以治疗包括T315I突变导致的耐药慢性粒细胞白血病。本研究在载脂蛋白E模拟多肽COG133的基础上设计了9条新的多肽并进行了活性筛选，得到1条活性明显优于COG133的多肽SP2。SP2对BaF3-p210(T315I)细胞作用72 h的IC₅₀为(2.9±0.1)μmol/L，是COG133［IC₅₀:(26.5±1.2)μmol/L］的十分之一。其作用机制是通过拮抗SET蛋白，提高细胞PP2A活性，使p-BCR-ABL1去磷酸化进而最终导致细胞凋亡。

Abstract: COG133, a peptide inhibitor of SET, can enhance PP2A activity to treat imatinib-resistant CML by T315I mutation. Based on this fact, a peptide designated as SP2 showed the best anti-tumor activity among nine newly-designed Apolipoprotein E-mimetic peptides compared to COG133. The IC₅₀ of SP2 against BaF3-p-210(T315I)cells was(2. 9±0. 1)μmol/L at 72 h, 10% of that of COG133(26. 5±1. 2 μmol/L). Further studies indicated that SP2 antagonizes SET protein to increase the activity of PP2A, thereby dephosphorylating p-BCR-ABL to induce cell apoptosis.