Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia

doi:10.1021/acs.jmedchem.1c01148

	Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia
	Han, Xu 1,2; Song, Ning1,2,3 ; Saidahmatov, Abdusaid 1,2; Wang, Peipei 1; Wang, Yong 1; Hu, Xiaobei 1,2,4; Kan, Weijuan 1; Zhu, Wei 1,2; Gao, Lixin 1; Zeng, Mingjie 1; Wang, Yujie 1; Li, Chunpu 1,2; Li, Jia1,2,3,4 ; Liu, Hong1,2,3 ; Zhou, Yubo 1,2,4; Wang, Jiang 1,2
	2021-10-14
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN	0022-2623
EISSN	1520-4804
卷号	64 期号:19 页码:14647-14663
DOI	10.1021/acs.jmedchem.1c01148
摘要	CDK9 is an essential drug target correlated to the development of acute myeloid leukemia (AML). Starting from the hit compound 10, which was discovered through a screening of our in-house compound library, the structural modifications were carried out based on the bioisosterism and scaffold hopping strategies. Consequently, compound 37 displayed the optimal CDK9 inhibitory activity with an IC50 value of 5.41 nM, which was nearly 1500-fold higher than compound 10. In addition, compound 37 exhibited significant antiproliferative activity in broad cancer cell lines. Further investigation of in vivo properties demonstrated that compound 37 could be orally administrated with an acceptable bioavailability (F = 33.7%). In MV-4-11 subcutaneous xenograft mouse model, compound 37 (7.5 mg/kg) could significantly suppress the tumor progression with a T/C value of 27.80%. Compound 37 represents a promising lead compound for the development of a novel class of CDK9 inhibitors for the treatment of acute myeloid leukemia.
收录类别	SCIE ; IC
语种	英语
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000709633100037
出版者	AMER CHEMICAL SOC
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/130326
专题	生命科学与技术学院_博士生生命科学与技术学院_特聘教授组_柳红组生命科学与技术学院_特聘教授组_李佳组
通讯作者	Liu, Hong; Zhou, Yubo; Wang, Jiang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Inst Drug Discovery Innovat, Zhongshan 528400, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Han, Xu,Song, Ning,Saidahmatov, Abdusaid,et al. Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(19):14647-14663.
APA	Han, Xu.,Song, Ning.,Saidahmatov, Abdusaid.,Wang, Peipei.,Wang, Yong.,...&Wang, Jiang.(2021).Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia.JOURNAL OF MEDICINAL CHEMISTRY,64(19),14647-14663.
MLA	Han, Xu,et al."Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia".JOURNAL OF MEDICINAL CHEMISTRY 64.19(2021):14647-14663.