Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion

Cyclin-dependent kinase 9 (CDK9) is an increasingly important potential cancer treatment target. Nowadays, developing selective CDK9 inhibitors has been extremely challenging as its ATP-binding sites are similar with other CDKs. Here, we report that the CDK9 inhibitor BAY-1143572 is converted into a series of proteolysis targeting chimeras (PROTACs) which leads to several compounds inducing the degradation of CDK9 in acute myeloid leukemia cells at a low nanomolar concentration. In addition, the most potent PROTAC molecule B03 could inhibit cell growth more effectively than warhead alone, with little inhibition of other kinases. This enhanced antiproliferative activity is mediated by a slight increase in kinase inhibitory activity and an increase in the level of apoptosis induction. Moreover, B03 could induce the degradation of CDK9 in vivo. Our work provides evidence that B03 represents a lead for further development and that CDK9 degradation is a potential valuable therapeutic strategy in acute myeloid leukemia. (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

CDK9 inhibitor BAY-1143572 converted into PROTACs leads to degradation of CDK9 in acute myeloid leukemia cells, with the most potent molecule B03 showing enhanced antiproliferative activity. This enhanced activity is mediated by increased kinase inhibitory activity and apoptosis induction levels. B03 can also induce CDK9 degradation in vivo, indicating its potential as a therapeutic strategy in acute myeloid leukemia.