College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
Molecules. 2020 May 8;25(9):2220. doi: 10.3390/molecules25092220.
Acute myeloid leukemia (AML) is among the top four malignancies in Saudi nationals, and it is the top leukemia subtype worldwide. Resistance to available AML drugs requires the identification of new targets and agents. Hsp90 is one of the emerging important targets in AML, which has a central role in the regulation of apoptosis and cell proliferation through client proteins including the growth factor receptors and cyclin dependent kinases. The objective of the first part of this study is to investigate the putative Hsp90 inhibition activity of three novel previously synthesized quinazolines, which showed HL60 cytotoxicity and VEGFR2 and EGFR kinases inhibition activities. Using surface plasmon resonance, compound 1 (HAA) showed better Hsp90 inhibition compared to 17-AAG, and a docking study revealed that it fits nicely into the ATPase site. The objective of the second part is to maximize the anti-leukemic activity of HAA, which was combined with each of the eleven standard inhibitors. The best resulting synergistic effect in HL60 cells was with the pan cyclin-dependent kinases (CDK) inhibitor dinaciclib, using an MTT assay. Furthermore, the inhibiting effect of the Hsp90α gene by the combination of HAA and dinaciclib was associated with increased caspase-7 and TNF-α, leading to apoptosis in HL60 cells. In addition, the combination upregulated p27 simultaneously with the inhibition of cyclinD3 and CDK2, leading to abolished HL60 proliferation and survival. The actions of HAA propagated the apoptotic and cell cycle control properties of dinaciclib, showing the importance of co-targeting Hsp90 and CDK, which could lead to the better management of leukemia.
急性髓系白血病 (AML) 是沙特国民中排名前四的恶性肿瘤之一，也是全球最常见的白血病亚型。对现有 AML 药物的耐药性要求确定新的靶点和药物。Hsp90 是 AML 中新兴的重要靶点之一，它通过包括生长因子受体和细胞周期蛋白依赖性激酶在内的客户蛋白在调节细胞凋亡和细胞增殖中发挥核心作用。本研究第一部分的目的是研究三种先前合成的喹唑啉的潜在 Hsp90 抑制活性，这些喹唑啉表现出 HL60 细胞毒性和 VEGFR2 和 EGFR 激酶抑制活性。使用表面等离子体共振，化合物 1（HAA）显示出比 17-AAG 更好的 Hsp90 抑制作用，并且对接研究表明它很好地适合于 ATP 结合位点。第二部分的目的是最大限度地提高 HAA 的抗白血病活性，将其与十一种标准抑制剂中的每一种结合。使用 MTT 测定法，在 HL60 细胞中与泛细胞周期蛋白依赖性激酶（CDK）抑制剂 dinaciclib 的组合产生了最佳的协同作用。此外，HAA 和 dinaciclib 组合对 Hsp90α 基因的抑制作用与 caspase-7 和 TNF-α 的增加有关，导致 HL60 细胞凋亡。此外，该组合同时上调了 p27，同时抑制了 cyclinD3 和 CDK2，导致 HL60 增殖和存活被消除。HAA 的作用传播了 dinaciclib 的凋亡和细胞周期控制特性，表明共靶向 Hsp90 和 CDK 的重要性，这可能导致白血病的更好管理。
