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Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia

文献类型：期刊论文

作者Jiang, Kailong1; Li, Xuemei2; Wang, Chang3; Hu, Xiaobei1,3; Wang, Peipei3,4; Tong, Lexian2,5,6; Tu, Yutong3,7; Chen, Beijing8; Jin, Tingting2,9; Wang, Tao10
刊名LEUKEMIA
出版日期2022-12-16
页码11
ISSN号0887-6924
DOI10.1038/s41375-022-01795-8
通讯作者Liu, Tao(lt601@zju.edu.cn) ; Li, Jia(jli@simm.ac.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn)
英文摘要FLT3 inhibitors (FLT3i) are widely used for the treatment of acute myeloid leukemia (AML), but adaptive and acquired resistance remains a primary challenge. Inhibitors simultaneously blocking adaptive and acquired resistance are highly demanded. Here, we observed the potential of CHK1 inhibitors to synergistically improve the therapeutic effect of FLT3i in FLT3-mutated AML cells. Notably, the combination overcame adaptive resistance. The simultaneous targeting of FLT3 and CHK1 kinases may overcome acquired and adaptive resistance. A dual FLT3/CHK1 inhibitor 30 with a good oral PK profile was identified. Mechanistic studies indicated that 30 inhibited FLT3 and CHK1, downregulated the c-Myc pathway and further activated the p53 pathway. Functional studies showed that 30 was more selective against cells with various FLT3 mutants, overcame adaptive resistance in vitro, and effectively inhibited resistant FLT3-ITD AML in vivo. Moreover, 30 showed favorable druggability without significant blood toxicity or myelosuppression and exhibited a good oral PK profile with a T-1/2 over 12 h in beagles. These findings support the targeting of FLT3 and CHK1 as a novel strategy for overcoming adaptive and acquired resistance to FLT3i therapy in AML and suggest 30 as a potential clinical candidate.
WOS关键词KINASE DOMAIN ; CHK1 ; ACTIVATION ; MUTATIONS ; DISCOVERY ; POTENT
资助项目Guangdong High-level new RD Institute[2019B090904008] ; Guangdong High-level Innovative Research Institute[2021B0909050003] ; key project of Zhejiang Provincial Natural Science Foundation of China[LZ21H300001] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[82204179] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19430750100]
WOS研究方向Oncology ; Hematology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:000899938300003
源URL[http://119.78.100.183/handle/2S10ELR8/303573]  
专题新药研究国家重点实验室
通讯作者Liu, Tao; Li, Jia; Zhou, Yubo
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
2.Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Zhejiang, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Jiangsu, Peoples R China
5.Zhejiang Univ, Sch Mat Sci & Engn, Hangzhou 310027, Zhejiang, Peoples R China
6.Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou 310018, Zhejiang, Peoples R China
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
8.Guizhou Med Univ, Sch Pharm, Guiyang 550025, Guizhou, Peoples R China
9.Zhejiang Univ, Affiliated Hangzhou Peoples Hosp 1, Translat Med Res Ctr, Sch Med, Hangzhou 310006, Zhejiang, Peoples R China
10.Naval Med Univ, Changhai Hosp, Shanghai 200433, Peoples R China
推荐引用方式
GB/T 7714		 Jiang, Kailong,Li, Xuemei,Wang, Chang,et al. Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia[J]. LEUKEMIA,2022:11.
APA Jiang, Kailong.,Li, Xuemei.,Wang, Chang.,Hu, Xiaobei.,Wang, Peipei.,...&Zhou, Yubo.(2022).Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia.LEUKEMIA,11.
MLA Jiang, Kailong,et al."Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia".LEUKEMIA (2022):11.

入库方式： OAI收割

来源：上海药物研究所

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