Gene

Kinase

Cell biology

Acute promyelocytic leukemia

Biology

Cell cycle

Cell culture

Retinoic acid

Cancer research

Biochemistry

Computer science

Protein kinase A

Leukemia

Computational biology

Immunology

Myeloid leukemia

Genetics

Cyclin-dependent kinase 2

Differentiation therapy

Artificial intelligence

Druggability

Medicine

Chemistry

Class (philosophy)

Cellular differentiation

Nature Chemical Biology

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.                                                                  A selective and potent CDK2 degrader was developed that induced differentiation of acute myeloid leukemia cell lines and primary patient cells.

Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy