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, Ning 1,2,3; 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
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-10-14
卷号	64 期号:19 页码:14647-14663
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.1c01148
通讯作者	Liu, Hong(hliu@simm.ac.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Wang, Jiang(jwang@simm.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[21877118] ; National Natural Science Foundation of China[81620108027] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19431908100]
WOS关键词	DEPENDENT KINASE INHIBITOR ; MANTLE-CELL LYMPHOMA ; CANCER ; FLAVOPIRIDOL ; POTENT ; CYCLE ; IDENTIFICATION ; TARGETS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000709633100037
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298689]
专题	中国科学院上海药物研究所
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
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.