Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models.
Li WangChen HuAoli WangCheng ChenJiaxin WuZongru JiangFengming ZouKailin YuHong WuJuan LiuWenliang WangZuowei WangBeilei WangZiping QiQingwang LiuWenchao WangLili LiJian GeJing LiuQing-Song LiuPublished in: Investigational new drugs (2019)
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.
Keyphrases
- acute myeloid leukemia
- cell cycle
- allogeneic hematopoietic stem cell transplantation
- clinical trial
- cell proliferation
- transcription factor
- gene expression
- emergency department
- small molecule
- acute lymphoblastic leukemia
- cell therapy
- cell death
- oxidative stress
- working memory
- heat stress
- heat shock
- double blind
- protein kinase