1. Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy.
- Author
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Wang L, Shao X, Zhong T, Wu Y, Xu A, Sun X, Gao H, Liu Y, Lan T, Tong Y, Tao X, Du W, Wang W, Chen Y, Li T, Meng X, Deng H, Yang B, He Q, Ying M, and Rao Y
- Subjects
- Antineoplastic Agents chemical synthesis, Aurora Kinase A genetics, Aurora Kinase A metabolism, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase 2 antagonists & inhibitors, Cyclin-Dependent Kinase 2 genetics, Cyclin-Dependent Kinase 2 metabolism, Drug Design, Drug Discovery, Humans, Ikaros Transcription Factor genetics, Ikaros Transcription Factor metabolism, Inhibitory Concentration 50, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Myeloid Progenitor Cells enzymology, Myeloid Progenitor Cells pathology, Piperazines pharmacology, Primary Cell Culture, Pyridines pharmacology, Pyrimidines pharmacology, Quinazolines pharmacology, Signal Transduction, Structure-Activity Relationship, Transcriptome, Triazoles chemical synthesis, Antineoplastic Agents pharmacology, Cell Differentiation drug effects, Gene Expression Regulation, Leukemic drug effects, Myeloid Progenitor Cells drug effects, Proteolysis drug effects, Triazoles pharmacology
- Abstract
The discovery of effective therapeutic treatments for cancer via cell differentiation instead of antiproliferation remains a great challenge. Cyclin-dependent kinase 2 (CDK2) inactivation, which overcomes the differentiation arrest of acute myeloid leukemia (AML) cells, may be a promising method for AML treatment. However, there is no available selective CDK2 inhibitor. More importantly, the inhibition of only the enzymatic function of CDK2 would be insufficient to promote notable AML differentiation. To further validate the role and druggability of CDK2 involved in AML differentiation, a suitable chemical tool is needed. Therefore, we developed first-in-class CDK2-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent CDK2 degradation in different cell lines without comparable degradation of other targets, and induced remarkable differentiation of AML cell lines and primary patient cells. These data clearly demonstrated the practicality and importance of PROTACs as alternative tools for verifying CDK2 protein functions.
- Published
- 2021
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