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Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy
- Source :
- Nature Chemical Biology. 17:567-575
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
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.
- Subjects :
- 0303 health sciences
Myeloid
Drug discovery
Cell growth
Cellular differentiation
030302 biochemistry & molecular biology
Druggability
Myeloid leukemia
Cell Biology
Biology
medicine.disease
03 medical and health sciences
Leukemia
medicine.anatomical_structure
Differentiation therapy
hemic and lymphatic diseases
Cancer research
medicine
Molecular Biology
030304 developmental biology
Subjects
Details
- ISSN :
- 15524469 and 15524450
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Nature Chemical Biology
- Accession number :
- edsair.doi...........8cca26991b99847983de809680e91a25