|
|||||
|
|
Design,Synthesis, and Biological Evaluation of 2-Aminothiazole Derivatives as Novel Checkpoint Kinase 1 (CHK1) Inhibitors |
|
| Authors: | Minjie Deng Peipei Wang Xiubing Long Gaoya Xu Chang Wang Dr Jia Li Dr Yubo Zhou Prof Tao Liu |
| Affiliation: | 1. College of Pharmaceutical Sciences, ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, 310058 Hangzhou, P. R. China
These authors contributed equally to this work.;2. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 210023 Nanjing, P. R. China State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, P. R. China These authors contributed equally to this work.;3. Wuxi Apptec Co., Ltd., 288 Fute Zhong Road, 200131 Shanghai, P. R. China These authors contributed equally to this work.;4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 210023 Nanjing, P. R. China State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, P. R. China;5. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, P. R. China;6. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 210023 Nanjing, P. R. China;7. College of Pharmaceutical Sciences, ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, 310058 Hangzhou, P. R. China |
| Abstract: | A series of 2-aminothiazole derivatives were designed, synthesized on the basis of bioisosterism strategy and evaluated for their CHK1 inhibitory activity. Most of them exhibited potent CHK1 inhibition, and excellent antiproliferative activity against MV-4-11 and Z-138 cell lines. Systematic structure-activity relationship (SAR) efforts led to the discovery of a promising compound 8 n , which showed potent CHK1 inhibitory activity with IC50 value of 4.25±0.10 nM, excellent antiproliferative activity against MV-4-11 and Z-138 cells with IC50 value of 42.10±5.77 nM and 24.16±6.67 nM, respectively, as well as moderate oral exposure (AUC(0−t)=1076.25 h ⋅ ng/mL) in mice. Additionally, treatment of MV-4-11 cells with compound 8 n for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Furthermore, kinase selectivity assay revealed that 8 n displayed acceptable selectivity toward 15 kinases. These results demonstrated that compound 8 n may be a promising potential anticancer agent for further development. |
| Keywords: | 2-aminothiazole CHK1 inhibitors antiproliferation hematologic malignancies biological activity |