Design, synthesis, and anticancer activity evaluation of irreversible allosteric inhibitors of the ubiquitin-conjugating enzyme Ube2g2.
Design, synthesis, and anticancer activity evaluation of irreversible allosteric inhibitors of the ubiquitin-conjugating enzyme Ube2g2.
复制标题
泛素结合酶 Ube2g2 不可逆变构抑制剂的设计、合成和抗癌活性评估。
作者：
Wang,Chao;Shi,Genbin;Ji,Xinhua
RING指依赖性泛素连接酶（E3）gp78，被称为肿瘤自分泌运动因子受体，有助于肿瘤进展。该蛋白通过其 RING 结构域和一个与 E2 强烈结合的称为 G2BR 的独特区域与其同源泛素结合酶 (E2) Ube2g2 相互作用。 G2BR 与 Ube2g2 的变构结合增强了 RING 与 E2 的结合，并且 RING 的结合也以变构方式触发 G2BR 从 E2 脱离。针对这些变构事件，我们开发了一系列抑制剂，它们不可逆地阻断 E2-E3 相互作用，从而消除 gp78 的致瘤作用。用 NCI 60 肿瘤细胞系筛选的 19 种化合物中有一种表现出出色的抗癌活性。 10 μM 时，它对 40% 的细胞系造成 >50% 的生长抑制；在 100 μM 时，它对大多数细胞系表现出致死活性。
The RING finger-dependent ubiquitin ligase (E3) gp78, known as the tumor autocrine motility factor receptor, contributes to tumor progression. The protein interacts with its cognate ubiquitin-conjugating enzyme (E2), Ube2g2, via its RING domain and a unique region called G2BR that strongly binds to E2. The binding of G2BR to Ube2g2 allosterically enhances the binding of RING to E2, and the binding of RING triggers the departure of G2BR from E2 also in an allosteric fashion. Targeting these allosteric events, we developed a family of inhibitors that irreversibly block E2–E3 interactions and thereby eliminate the tumorigenic effect of gp78. One among 19 compounds screened with the NCI 60 tumor cell lines exhibited outstanding anticancer activities. At 10 μM, it caused >50% growth inhibition to 40% of the cell lines; at 100 μM, it showed lethiferous activity against most cell lines.