Design, Synthesis, and Biological Evaluation of 2‐Aminothiazole Derivatives as Novel Checkpoint Kinase 1 (CHK1) Inhibitors

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 structu...

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Published in:ChemMedChem 2023-04, Vol.18 (7), p.e202200664-n/a
Main Authors: Deng, Minjie, Wang, Peipei, Long, Xiubing, Xu, Gaoya, Wang, Chang, Li, Jia, Zhou, Yubo, Liu, Tao
Format: Article
Language:English
Subjects:
2-aminothiazole
Animals
Anticancer properties
Antineoplastic Agents - pharmacology
antiproliferation
Antiproliferatives
Antitumor agents
biological activity
Blood cancer
Cell Line, Tumor
Cell lines
Cell Proliferation
Checkpoint Kinase 1
CHK1 inhibitors
CHK1 protein
Drug Design
Drug Screening Assays, Antitumor
hematologic malignancies
Kinases
Mice
Molecular Structure
Protein Kinase Inhibitors - pharmacology
Structure-Activity Relationship
Thiazoles - pharmacology
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Summary: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. Anticancer agents: In this work, a series of 2‐aminothiazole derivatives were designed as novel CHK1 inhibitors by using a bioisosterism strategy. The most promising compound 8 n (shown) exhibited potent CHK1 inhibition, excellent anti‐proliferative activity on MV‐4‐11 cells, and favourable PK profiles.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202200664