Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139 Milan, Italy.
Bioorg Chem. 2021 Dec;117:105451. doi: 10.1016/j.bioorg.2021.105451. Epub 2021 Oct 24.
Aurora B is a pivotal cell cycle regulator where errors in its function results in polyploidy, genetic instability, and tumorigenesis. It is overexpressed in many cancers, consequently, targeting Aurora B with small molecule inhibitors constitutes a promising approach for anticancer therapy. Guided by structure-based design and molecular hybridization approach we developed a series of fifteen indolin-2-one derivatives based on a previously reported indolin-2-one-based multikinase inhibitor (1). Seven derivatives, 5g, 6a, 6c-e, 7, and 8a showed preferential antiproliferative activity in NCI-60 cell line screening and out of these, carbamate 6e and cyclopropylurea 8a derivatives showed optimum activity against Aurora B (IC = 16.2 and 10.5 nM respectively) and MDA-MB-468 cells (IC = 32.6 ± 9.9 and 29.1 ± 7.3 nM respectively). Furthermore, 6e and 8a impaired the clonogenic potential of MDA-MB-468 cells. Mechanistic investigations indicated that 6e and 8a induced G2/M cell cycle arrest, apoptosis, and necrosis of MDA-MB-468 cells and western blot analysis of 8a effect on MDA-MB-468 cells revealed 8a's ability to reduce Aurora B and its downstream target, Histone H3 phosphorylation. 6e and 8a displayed better safety profiles than multikinase inhibitors such as sunitinib, showing no cytotoxic effects on normal rat cardiomyoblasts and murine hepatocytes. Finally, 8a demonstrated a more selective profile than 1 when screened against ten related kinases. Based on these findings, 8a represents a promising candidate for further development to target breast cancer via Aurora B selective inhibition.
极光 B 是一个关键的细胞周期调节剂，其功能的错误会导致多倍体、遗传不稳定性和肿瘤发生。它在许多癌症中过表达，因此，用小分子抑制剂靶向 Aurora B 是一种很有前途的抗癌治疗方法。在基于结构的设计和分子杂交方法的指导下，我们根据之前报道的基于吲唑-2-酮的多激酶抑制剂（1）开发了一系列 15 个吲唑-2-酮衍生物。在 NCI-60 细胞系筛选中，7 个衍生物 5g、6a、6c-e、7 和 8a 显示出对增殖的优先抑制活性，其中，氨基甲酸酯 6e 和环丙基脲 8a 衍生物对 Aurora B（IC = 16.2 和 10.5 nM 分别）和 MDA-MB-468 细胞（IC = 32.6 ± 9.9 和 29.1 ± 7.3 nM 分别）显示出最佳的活性。此外，6e 和 8a 损害了 MDA-MB-468 细胞的集落形成能力。机制研究表明，6e 和 8a 诱导 MDA-MB-468 细胞的 G2/M 细胞周期停滞、凋亡和坏死，并且 8a 对 MDA-MB-468 细胞的 Western blot 分析表明，8a 能够降低 Aurora B 及其下游靶标组蛋白 H3 的磷酸化。6e 和 8a 比多激酶抑制剂（如舒尼替尼）具有更好的安全性特征，对正常大鼠心肌细胞和小鼠肝细胞没有细胞毒性作用。最后，在筛选针对十种相关激酶时，8a 比 1 具有更选择性的谱。基于这些发现，8a 代表了通过 Aurora B 选择性抑制进一步开发针对乳腺癌的有前途的候选药物。
