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

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

  • Invest New Drugs. 2020 Oct;38(5):1272-1281. doi: 10.1007/s10637-019-00868-3.
Li Wang  # 1 2,  Chen Hu  # 1 2,  Aoli Wang  # 1 3,  Cheng Chen  # 1 2,  Jiaxin Wu  # 1 2,  Zongru Jiang 1 2,  Fengming Zou 1 3,  Kailin Yu 1 3,  Hong Wu 1 3,  Juan Liu 1 2,  Wenliang Wang 1 2,  Zuowei Wang 1 2,  Beilei Wang 1 2,  Ziping Qi 1 3,  Qingwang Liu 3 4,  Wenchao Wang 1 3 4,  Lili Li 5,  Jian Ge 6,  Jing Liu 7 8 9,  Qingsong Liu 10 11 12 13 14
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, People's Republic of China.
  • 2 University of Science and Technology of China, Hefei, Anhui, 230036, People's Republic of China.
  • 3 Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, People's Republic of China.
  • 4 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, People's Republic of China.
  • 5 Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People's Republic of China.
  • 6 Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People's Republic of China. [email protected].
  • 7 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, People's Republic of China. [email protected].
  • 8 Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, People's Republic of China. [email protected].
  • 9 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, People's Republic of China. [email protected].
  • 10 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, People's Republic of China. [email protected].
  • 11 University of Science and Technology of China, Hefei, Anhui, 230036, People's Republic of China. [email protected].
  • 12 Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, People's Republic of China. [email protected].
  • 13 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, People's Republic of China. [email protected].
  • 14 Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, 230601, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 31872348 DOI: 10.1007/s10637-019-00868-3
Abstract

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.

Keywords

Acute myeloid leukemia; CDK9 kinase; Transcription addiction.

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