2. Academic Validation
  3. Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor

Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2-methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor

  • Eur J Med Chem. 2018 Oct 5;158:896-916. doi: 10.1016/j.ejmech.2018.09.025.
Beilei Wang 1,  Jiaxin Wu 1,  Yun Wu 2,  Cheng Chen 1,  Fengming Zou 2,  Aoli Wang 2,  Hong Wu 2,  Zhenquan Hu 2,  Zongru Jiang 1,  Qingwang Liu 3,  Wei Wang 2,  Yicong Zhang 1,  Feiyang Liu 2,  Ming Zhao 4,  Jie Hu 4,  Tao Huang 4,  Juan Ge 4,  Li Wang 1,  Tao Ren 4,  Yuxin Wang 5,  Jing Liu 6,  Qingsong Liu 7
Affiliations

Affiliations

  • 1 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230036, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China.
  • 2 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China.
  • 3 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, PR China.
  • 4 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China.
  • 5 Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China.
  • 6 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China. Electronic address: jingliu@hmfl.ac.cn.
  • 7 High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230036, PR China; Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230088, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China; Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, 230601, PR China. Electronic address: qsliu97@hmfl.ac.cn.
PMID: 30253346 DOI: 10.1016/j.ejmech.2018.09.025
Abstract

Through a structure-guided rational drug design approach, we have discovered a highly selective inhibitor compound 40 (JSH-150), which exhibited an IC50 of 1 nM against CDK9 kinase in the biochemical assay and achieved around 300-10000-fold selectivity over other CDK kinase family members. In addition, it also displayed high selectivity over other 468 kinases/mutants (KINOMEscan S score(1) = 0.01). Compound 40 displayed potent antiproliferative effects against melanoma, neuroblastoma, hepatoma, colon Cancer, lung Cancer as well as leukemia cell lines. It could dose-dependently inhibit the phosphorylation of RNA Pol II, suppress the expression of Mcl-1 and c-Myc, arrest the cell cycle and induce the Apoptosis in the leukemia cells. In the MV4-11 cell-inoculated xenograft mouse model, 10 mg/kg dosage of 40 could almost completely suppress the tumor progression. The high selectivity and good in vivo PK/PD profile suggested that 40 would be a good pharmacological tool to study CDK9-mediated physiology and pathology as well as a potential drug candidate for leukemia and other cancers.

Keywords

1,2-Dimethoxyethane; 4-Dimethylaminopyridine; AML; Acute myeloid leukemia; CDK; CDK9; CLL; Chronic lymphocytic leukemia; Cyclin-dependent kinase; DCM; DIAD; DIPEA; DMAP; DME; DMF; DMSO; Diisopropyl azodicarboxylate; Dimethyl chloride; Dimethyl sulfoxide; Kinase inhibitor; LDA; Leukemia; Lithium diisopropylamide; MCL; Mantle cell lymphoma; N; N-bromobutanimide; N-diisopropylethylamine; N-dimethylformamide; NBS; SAR; Structure-activity relationship.

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