Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models

Summary Acute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvoc...

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Bibliographic Details
Published in:Investigational new drugs 2020-10, Vol.38 (5), p.1272-1281
Main Authors: Wang, Li, Hu, Chen, Wang, Aoli, Chen, Cheng, Wu, Jiaxin, Jiang, Zongru, Zou, Fengming, Yu, Kailin, Wu, Hong, Liu, Juan, Wang, Wenliang, Wang, Zuowei, Wang, Beilei, Qi, Ziping, Liu, Qingwang, Wang, Wenchao, Li, Lili, Ge, Jian, Liu, Jing, Liu, Qingsong
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Addictions
Anticancer properties
Antitumor activity
Clinical trials
Cyclin-dependent kinase
Cyclin-dependent kinase 9
Cyclin-dependent kinases
Elongation
Enzyme inhibitors
Flavopiridol
Inhibitors
Kinases
Leukemia
Medicine
Medicine & Public Health
Myeloid leukemia
Oncology
Pharmacology/Toxicology
Preclinical Studies
Selectivity
Therapeutic targets
Transcription elongation
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Summary:Summary Acute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvocidib and dinaciclib, have shown potent therapeutic effects in clinical trials on AML, the lack of high selectivity for CDK9 and other CDKs has limited their optimal clinical efficacy. Therefore, developing highly selective CDK9 inhibitors is still imperative for the efficacy and safety profile in treating AML. Here, we report a novel highly selective CDK9 inhibitor, JSH-009, which exhibited high potency against CDK9 and displayed great selectivity over 468 kinases/mutants. It also demonstrates impressive in vitro and in vivo antileukemic efficacy in preclinical models of AML, which makes JSH-009 a useful pharmacological tool for elucidating CDK9-mediated transcription and a novel therapeutic candidate for AML.
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-019-00868-3