ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China.
Jiangsu Shengdia Industrial Co. Ltd., NO. 161 Shaoxing Road, Xiacheng District, Hangzhou, 310004, PR China.
Eur J Med Chem. 2021 Oct 5;221:113556. doi: 10.1016/j.ejmech.2021.113556. Epub 2021 May 25.
A series of epoxyketone analogues with varying N-caps and P3-configurations were designed, synthesized and evaluated. We found that D-Ala in P3 was crucial for β5i selectivity over β5c. Notably, compounds 20j (β5i IC = 26.0 nM, 25-fold selectivity) and 20l (β5i IC = 25.1 nM, 24-fold selectivity) with the D-configuration at P3 were the most selective inhibitors. Although 20j and 20l showed only moderate anti-proliferative activity against RPMI-8226 and MM.1S cell lines, based on our experiments, it indicates that the inhibition of β5i alone is not sufficient to exert anticancer effects and may rely on the complementary inhibition of β1i, β5c and β5i. These data further increase our understanding of immunoproteasome inhibitors in hematologic malignancies.
我们设计、合成并评估了一系列具有不同 N-帽和 P3-构象的环氧化酮类似物。我们发现 P3 中的 D-Ala 对于β5i 选择性至关重要，超过了β5c。值得注意的是，具有 D-构型的化合物 20j（β5i IC = 26.0 nM，25 倍选择性）和 20l（β5i IC = 25.1 nM，24 倍选择性）是最具选择性的抑制剂。尽管化合物 20j 和 20l 对 RPMI-8226 和 MM.1S 细胞系仅表现出中等的抗增殖活性，但根据我们的实验，这表明单独抑制β5i 不足以发挥抗癌作用，可能依赖于对β1i、β5c 和β5i 的互补抑制。这些数据进一步加深了我们对血液恶性肿瘤中免疫蛋白酶体抑制剂的理解。
