Published in:
01-10-2020 | Acute Myeloid Leukemia | PRECLINICAL STUDIES
Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models
Authors:
Li Wang, Chen Hu, Aoli Wang, Cheng Chen, Jiaxin Wu, Zongru Jiang, Fengming Zou, Kailin Yu, Hong Wu, Juan Liu, Wenliang Wang, Zuowei Wang, Beilei Wang, Ziping Qi, Qingwang Liu, Wenchao Wang, Lili Li, Jian Ge, Jing Liu, Qingsong Liu
Published in:
Investigational New Drugs
|
Issue 5/2020
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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.