1. Academic Validation
  2. 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

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

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: Lt601@zju.edu.cn.
  • 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: jli@simm.ac.cn.
  • 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: huyz@zju.edu.cn.
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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