Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino)pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies

  • Eur J Med Chem. 2019 Jul 1;173:44-62. doi: 10.1016/j.ejmech.2019.03.062.
Lexian Tong  1 ,  Pinrao Song  2 ,  Kailong Jiang  3 ,  Lei Xu  4 ,  Tingting Jin  1 ,  Peipei Wang  3 ,  Xiaobei Hu  3 ,  Sui Fang  5 ,  Anhui Gao  3 ,  Yubo Zhou  3 ,  Tao Liu  6 ,  Jia Li  7 ,  Yongzhou Hu  8
Affiliations
  • 1. ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 2. Shanghai Haini Pharmaceutical Co. Ltd., Yangtze River Pharmaceutical Group, Shanghai, 201318, PR China.
  • 3. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China.
  • 4. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China; ShanghaiTech University, Shanghai, 201210, PR China.
  • 5. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China.
  • 6. ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: [email protected].
  • 7. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China; ShanghaiTech University, Shanghai, 201210, PR China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao, 266237, PR China. Electronic address: [email protected].
  • 8. ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: [email protected].
PMID: 30986571 DOI: 10.1016/j.ejmech.2019.03.062
Abstract

Through virtual screening, we identified the lead compound MCL1020, which exhibited modest Chk1 inhibitory activity. Then a series of 5-(pyrimidin-2-ylamino)picolinonitrile derivatives as Chk1 inhibitors were discovered by further rational optimization. One promising molecule, (R)-17, whose potency was one of the best, had an IC50 of 0.4 nM with remarkable selectivity (>4300-fold Chk1 vs. Chk2). Compound (R)-17 effectively inhibited the growth of malignant hematopathy cell lines especially Z-138 (IC50: 0.013 μM) and displayed low affinity for hERG (IC50 > 40 μM). Moreover, (R)-17 significantly suppressed the tumor growth in Z-138 cell inoculated xenograft model (20 mg/kg I.V., TGI = 90.29%) as a single agent with body weight unaffected. Taken together, our data demonstrated compound (R)-17 could be a promising drug candidate for the treatment of hematologic malignancies.

Keywords
CHK1 kinase inhibitor; Hematologic malignancies; Monotherapy; Selectivity.
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