吡唑并嘧啶类PI3Kγ/δ抑制剂的合成及抗肿瘤活性研究  

Synthesis and anti-tumor activity of pyrazole pyrimidine PI3Kγ/δinhibitors

作　　者：邓茂青 邹凤鸣 齐紫平 王纯 龙凯丽 刘青旺 王傲莉[1,3] 刘静 梁小飞[1,2,3] DENG Mao-qing;ZOU Feng-ming;QI Zi-ping;WANG Chun;LONG Kai-li;LIU Qing-wang;WANG Ao-li;LIU Jing;LIANG Xiao-fei(Institute of Health and Medical Technology,Hefei Institutes of Physical Science,Chinese Academy of Sciences,Hefei 230031,China;University of Science and Technology of China,Hefei 230026,China;Hefei Cancer Hospital,Chinese Academy of Sciences,Hefei 230031,China)

机构地区：[1]中国科学院,合肥物质科学研究院健康与医学技术研究所,安徽合肥230031 [2]中国科学技术大学,安徽合肥230026 [3]中国科学院合肥肿瘤医院,安徽合肥230031

出　　处：《药学学报》2024年第7期2041-2052,共12页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金项目(82173671,82373723,81872745);安徽省自然科学基金项目(2108085J42);安徽省重点研究与开发计划项目(2023s07020018)。

摘　　要：PI3Kγ和PI3Kδ在免疫系统中有重要的调控作用,靶向这两个亚型有助于重塑肿瘤微环境。PI3Kγ和PI3Kδ是肿瘤免疫治疗的潜在靶点,本研究在前期工作的基础上,设计合成了16个新型吡唑并嘧啶类化合物并发现了PI3Kγ/δ双重抑制剂16l。体外研究表明,化合物16l在蛋白和细胞水平具有良好的活性和选择性。在蛋白层次16l对PI3Kγ和PI3Kδ的抑制活性分别为0.11和0.79 nmol·L-1;在细胞层次16l抑制PI3K Akt S473的磷酸化,对PI3Kγ和PI3Kδ的抑制活性分别为3和7 nmol·L-1。体内研究表明,在Sprague-Dawley(SD)大鼠上,化合物16l具有良好的药代动力学性质。在MC38同种移植小鼠模型上,化合物16l能够激活小鼠的免疫系统,并显著抑制肿瘤生长。动物实验得到了中国科学院合肥物质科学研究院动物伦理委员会的批准(批准号:DWLL-2000-06)。同时,人类ethera-go-go相关基因(human ether-a-go-go-related gene,hERG)实验表明16l没有明显的潜在心脏毒性。本研究为深入了解PI3Kγ/δ的病理和生理功能提供了工具分子,为靶向PI3Kγ/δ的小分子免疫治疗药物的研发提供了苗头化合物。PI3Kγand PI3Kδhave important regulatory roles in the immune system,and targeting these two subtypes helps to reshape the tumor microenvironment.PI3Kγand PI3Kδare potential targets for tumor immunotherapy.In this study,a series of new pyrazolopyrimidine derivatives were designed and synthesized on the basis of our previously reported PI3K inhibitors,resulting in the discovery of compound 16l as a potent and selective PI3Kγ/δdual inhibitor.Compound 16l demonstrated strong biochemical potencies against PI3Kγand PI3Kδwith IC 50 values of 0.11 and 0.79 nmol·L-1.In cell-based assays,it potently inhibited the PI3Kγand PI3Kδmediated Akt S473 phosphorylation with EC 50 values of 3 and 7 nmol·L-1.In vivo,compound 16l exhibited acceptable pharmacokinetic properties in Sprague-Dawley(SD)rats and suppressed the tumor growth in a MC38 syngeneic mouse model.The animal experiments were approved by the Animal Ethics Committee of Hefei Institutes of Physical Science,Chinese Academy of Sciences(approval number:DWLL-2000-06).In addition,no appreciable human ether-a-go-go-related gene(hERG)inhibition was observed for compound 16l even at 30μmol·L-1.These results suggested that compound 16l might be a potential research tool for studying the PI3Kγ/δmediated signaling pathways.

关 键 词：PI3Kγ PI3Kδ 肿瘤微环境 吡唑并嘧啶 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]