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Design,Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia |
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| Authors: | Tingting Jin Peipei Wang Xiubing Long Dr Kailong Jiang Dr Pinrao Song Wenbiao Wu Gaoya Xu Dr Yubo Zhou Dr Jia Li Prof Tao Liu |
| Affiliation: | 1. College of Pharmaceutical Sciences, ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou, 310058 P. R. China
These authors contributed equally to this work.;2. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 P. R. China These authors contributed equally to this work.;3. College of Pharmaceutical Sciences, ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou, 310058 P. R. China;4. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 P. R. China University of Chinese Academy of Sciences, No. 19?A Yuquan Road, Beijing, 100049 P. R. China;5. Shanghai Jemincare Pharmaceuticals Co. Ltd, Jemincare Group Research Institute, 1118 Halei Road, Shanghai, 201203 P. R. China;6. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203 P. R. China |
| Abstract: | Checkpoint kinase 1 (CHK1) is a central component in DNA damage response and has emerged as a target for antitumor therapeutics. Herein, we describe the design, synthesis, and biological evaluation of a novel series of potent diaminopyrimidine CHK1 inhibitors. The compounds exhibited moderate to potent CHK1 inhibition and could suppress the proliferation of malignant hematological cell lines. The optimized compound 13 had a CHK1 IC50 value of 7.73±0.74 nM, and MV-4-11 cells were sensitive to it (IC50=0.035±0.007 μM). Furthermore, compound 13 was metabolically stable in mouse liver microsomes in vitro and displayed moderate oral bioavailability in vivo. Moreover, treatment of MV-4-11 cells with compound 13 for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Based on these biochemical results, we consider compound 13 to be a promising CHK1 inhibitor and potential anticancer therapeutic agent. |
| Keywords: | CHK1 inhibitor diaminopyrimidine DNA damage response oral bioavailability |