Wang Quan, Hu XiaoLong, Shi Wei, Long Huan, Wang Hao
State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
State Key Laboratory of Natural Medicines, Department of TCM Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
Bioorg Med Chem Lett. 2022 Aug 1;69:128799. doi: 10.1016/j.bmcl.2022.128799. Epub 2022 May 14.
Protein kinase CK2 is a potential target for the discovery of anticancer drugs. Flavonoids are reported to be effective CK2 inhibitors. Herein, based on structural trimming of flavonoids, a series of chromone-2-aminothiazole derivatives (1a-d, 2a-g, 4a-j, 5a-k) were designed and synthesized by hybridizing the chromone skeleton with 2-aminothiazole scaffold. Among these compounds, compound 5i was the most effective CK2 inhibitor (IC = 0.08 μM) and possessed potent anti-proliferative activity against HL-60 tumor cells (IC = 0.25 μM). Cellular thermal shift assay (CESTA) confirmed that 5i directly bound to the CK2, and the possible binding mode of 5i toward CK2 was also simulated. Further studies showed that 5i induced the apoptosis of HL-60 cells and arrested the cell cycle. Finally, western-blot analysis showed that 5i could inhibit the downstream of CK2, including α-catenin/Akt pathway and PARP/Survivin pathway.
蛋白激酶CK2是抗癌药物发现的潜在靶点。据报道，黄酮类化合物是有效的CK2抑制剂。在此，基于黄酮类化合物的结构修饰，通过将色酮骨架与2-氨基噻唑支架杂交，设计并合成了一系列色酮-2-氨基噻唑衍生物（1a-d、2a-g、4a-j、5a-k）。在这些化合物中，化合物5i是最有效的CK2抑制剂（IC = 0.08 μM），对HL-60肿瘤细胞具有强大的抗增殖活性（IC = 0.25 μM）。细胞热位移分析（CETSA）证实5i直接与CK2结合，并且还模拟了5i与CK2的可能结合模式。进一步的研究表明，5i诱导HL-60细胞凋亡并使细胞周期停滞。最后，蛋白质印迹分析表明5i可以抑制CK2的下游，包括α-连环蛋白/Akt途径和PARP/生存素途径。
