Fan Yanhua, Zhang Feng, Xiong Liang, Su Mingzhi, Luo Fang, Li Mei, Li Qing, Zhong Ting, Yuan Meitao, Xu Yongnan, Mu Shuzhen, Yang Huarong
State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China.
State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China.
Bioorg Chem. 2023 Jun;135:106484. doi: 10.1016/j.bioorg.2023.106484. Epub 2023 Mar 20.
ROR1 and Aurora kinase were overexpressed in various cancers and essential for cell proliferation, survive and metastasis. Pharmaceutical inhibition of ROR1 and Aurora kinase abrogated the activation of downstream signaling and induced cancer cell apoptosis. Hence, ROR1 and Aurora kinase considered as attractive therapeutic targets for the development of anticancer drugs. In the present work, three series of novel 6-(imidazo[1,2-a] pyridin-6-yl)-quinazolin-4(3H)-one derivatives were designed and synthesized via bioisosterism and scaffold-hopping strategies guided by FLF-13, an Aurora kinase inhibitor we discovered earlier. Most of compounds in series 2 and series 3 showed submicromolar to nanomolar inhibitory activity against multiple cancer cell lines. More importantly, compounds 12d and 12f in series 3 showed nanomolar inhibitory activity against all test cancer cells. The most promising compound 12d exhibited potent inhibitory activity against Aurora A and Aurora B with IC values of 84.41 nM and 14.09 nM, respectively. Accordingly, compounds 12d induced G2/M phase cell cycle arrest at 24 h and polyploidy at 48 h. It's worth noting that 12d also displayed inhibitory activity against ROR1 and induce cell apoptosis. Furthermore, 12d could significantly inhibit the tumor growth in SH-SY5Y xenograft model with tumor growth inhibitory rate (IR) up to 46.31 % at 10 mg/kg and 52.66 % at 20 mg/kg. Overall, our data suggested that 12d might serve as a promising candidate for the development of therapeutic agents for cancers with aberrant expression of ROR1 and Aurora kinases by simultaneously targeting ROR1 and Aurora kinase.
ROR1和Aurora激酶在多种癌症中过表达，对细胞增殖、存活和转移至关重要。对ROR1和Aurora激酶的药物抑制消除了下游信号的激活并诱导癌细胞凋亡。因此，ROR1和Aurora激酶被认为是开发抗癌药物有吸引力的治疗靶点。在本研究中，通过生物电子等排体和骨架跃迁策略，以我们先前发现的Aurora激酶抑制剂FLF-13为指导，设计并合成了三个系列的新型6-(咪唑并[1,2-a]吡啶-6-基)-喹唑啉-4(3H)-酮衍生物。系列2和系列3中的大多数化合物对多种癌细胞系表现出亚微摩尔至纳摩尔的抑制活性。更重要的是，系列3中的化合物12d和12f对所有测试癌细胞均表现出纳摩尔抑制活性。最有前景的化合物12d对Aurora A和Aurora B表现出强效抑制活性，IC值分别为84.41 nM和14.09 nM。因此，化合物12d在24小时诱导G2/M期细胞周期停滞，在48小时诱导多倍体形成。值得注意的是，12d还对ROR1表现出抑制活性并诱导细胞凋亡。此外，12d在SH-SY5Y异种移植模型中可显著抑制肿瘤生长，在10 mg/kg时肿瘤生长抑制率（IR）高达46.31%，在20 mg/kg时为52.66%。总体而言，我们的数据表明，12d可能通过同时靶向ROR1和Aurora激酶，成为开发用于治疗ROR1和Aurora激酶异常表达癌症的治疗药物的有前景候选物。
