Design,Synthesis,and Biological Evaluation Of 2-aminothiazole/3-aminopyrazole Derivatives As CHK1 Inhibitors

Checkpoint kinase 1（CHK1）plays an important role in the process of DNA damage response.When DNA damage occurs,it can cause cell cycle arrest and provide time for repair of the damaged DNA.Therefore,CHK1 has become an important target for tumor treatment.Clinically,CHK1 inhibitors are mainly used as chemotherapy or radiotherapy sensitizers to improve the therapeutic effect.For some tumors with potential DNA damage repair defects,such as leukemia,lymphoma,melanoma,etc.CHK1 inhibitors can also exert an anti-tumor activity when used alone.Most compounds were discontinued after early clinical trials due to low efficacy or toxic side effects,and only four CHK1 inhibitors are currently in clinical trials.In order to discover novel CHK1 inhibitors,compound MCL1020 previously obtained by the virtual screening of our research group was used as the lead compound.In order to improve pharmacological profiles and biological activity,the following two types of compounds with new structures were designed and synthesized by using the strategy of scaffold hopping and rational drug design:2-Aminothiazoles derivatives:A total of 38 compounds were tested for CHK1kinase inhibitory activity.Most compounds showed moderate to strong CHK1 inhibitory activity,and the IC₅₀ values of 20 compounds were less than 20 n M.Compounds I-32 and I-38 were better than the positive control GDC-0575,and their IC₅₀ values were 1.86 n M and 1.71 n M,respectively.The compounds with greatinhibitory activity of CHK1 were selected to test the anti-proliferation activity against MV4-11,THP-1,and Z-138 cell lines.Most of the compounds had moderate to strong anti-proliferation activities on MV4-11 and Z-138 cell lines,and the anti-proliferation activities on THP-1 cell line were relatively weak.Among them,the anti-proliferation activity of compound I-32 on MV4-11 cells was equivalent to that of GDC-0575,and the anti-proliferation activities of compounds I-15,I-38,I-39,and I-40 on MV4-11cells were better than GDC-0575.The stability test of mouse liver microsomes showed that compounds I-15,I-32,I-38,and I-40 had good metabolic stability.The pharmacokinetic test showed that I-15 had good PK properties,and the oral exposure AUC_（0-∞）was 1103.75 h·ng/m L（10 mg/kg,po）.Overall,compound I-15 wasworth further study.3-Aminopyrazoles derivatives:A total of 6 compounds showed moderate to strong inhibitory activities.Among them,compound I-45 was superior to GDC-0575,and the IC₅₀ value was 0.89 n M.5 compounds with good inhibitory activity were selected to test the proliferation inhibitory activity of MV4-11 and Z-138 cell lines.The results showed that the anti-proliferation activity of compound I-45 on Z-138 cell lines was similar to that of GDC-0575.The IC₅₀ values of compounds I-45 and I-46on MV4-11 cell lines were 44.41 n M and 20.62 n M,respectively,which were better than those of GDC-0575.The stability test of mouse liver microsomes showed that compounds I-45 and I-46 had great metabolic stability and had the potential for further research.Besides,GDC-0575 was selected as the lead compound in this study.Based on the binding mode of CHK1 inhibitor and CHK1 protein,a total of 15 7-azaindole and2-aminopyridine derivatives were designed and synthesized by ring-opening and rational drug design strategies.However,in vitro kinase activity test showed that these compounds had weak inhibitory activity against CHK1.Therefore,the study of novel CHK1 inhibitors need further exploration.