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
  • 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: [email protected].
  • 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: [email protected].
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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