Discovery of Novel [1,2,4]Triazolo[1,5- a]pyrimidine Derivatives as Novel Potent S-Phase Kinase-Associated Protein 2 (SKP2) Inhibitors for the Treatment of Cancer

Kaizhao Hu; Yongqiang Luo; Peipei Miao; Lidan Zhao; Bing Zhao; Xiao-Jing Shi; Hong-Min Liu

doi:10.1021/acs.jmedchem.4c01283

Discovery of Novel [1,2,4]Triazolo[1,5- a]pyrimidine Derivatives as Novel Potent S-Phase Kinase-Associated Protein 2 (SKP2) Inhibitors for the Treatment of Cancer

J Med Chem. 2024 Sep 26;67(18):16435-16454. doi: 10.1021/acs.jmedchem.4c01283. Epub 2024 Sep 16.

Authors

Kaizhao Hu^{1

2}, Yongqiang Luo², Peipei Miao¹, Lidan Zhao¹, Bing Zhao², Xiao-Jing Shi¹, Hong-Min Liu²

Affiliations

¹ Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Laboratory Animal Center, State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province 450052, P. R. China.
² Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China; Key Laboratory of Henan Province for Drug Quality and Evaluation; Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.

PMID: 39285177
DOI: 10.1021/acs.jmedchem.4c01283

Abstract

Skp1-CUL1-ROC1-F-box E3 ubiquitin ligases' main component S-phase kinase-associated protein 2 (Skp2) is responsible for specifically recognizing ubiquitination-modified substrates to be degraded such as p27 and p21 in the case of binding with adaptor protein Cks1. Pharmacological inhibition of Skp2 has exhibited promising antitumor activity. Herein, we present the design and optimization of a series of [1,2,4]triazolo[1,5-a]pyrimidine-based small molecules targeting Skp2. Among them, E35 demonstrated excellent inhibitory activities against the binding of Skp2-Cks1. In addition, compound E35 significantly inhibited colony formation and migration, as well as arrested the cell cycle at the S-phase. Mechanistically, compound E35 markedly decreased the expression of Skp2, as well as increased the expression of its substrates p21 and p27. Furthermore, compound E35 showed an obvious inhibitory effect on MGC-803 xenograft mice without obvious toxicity. All of these results suggest that compound E35 might be a valuable lead compound for antitumor agents targeting Skp2.

MeSH terms

Animals
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
CDC2-CDC28 Kinases / antagonists & inhibitors
CDC2-CDC28 Kinases / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Discovery
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Pyrimidines* / chemical synthesis
Pyrimidines* / chemistry
Pyrimidines* / pharmacology
Pyrimidines* / therapeutic use
S-Phase Kinase-Associated Proteins* / antagonists & inhibitors
S-Phase Kinase-Associated Proteins* / metabolism
Structure-Activity Relationship
Triazoles / chemical synthesis
Triazoles / chemistry
Triazoles / pharmacology
Triazoles / therapeutic use
Xenograft Model Antitumor Assays

Substances

S-Phase Kinase-Associated Proteins
Pyrimidines
Antineoplastic Agents
SKP2 protein, human
Triazoles
Protein Kinase Inhibitors
CDC2-CDC28 Kinases
CKS1B protein, human