Oncogenic mutations in gene encoding FLT3 kinase are often detected in acute myeloid leukaemia (AML) patients, and several potent kinase inhibitors have been developed. However, the FLT3 inhibitor treatment often leads to the resistance development and subsequent relapse. Targeted degradation of oncogenic protein kinases has emerged as a feasible pharmacological strategy, providing more robust effect over traditional competitive inhibitors. Based on previously developed competitive inhibitor of FLT3 and CDK9, we have designed and prepared a novel pomalidomide-based PROTAC. A series of biochemical and cellular experiments showed selectivity towards FLT3-ITD bearing AML cells and confirmed proteasome-dependent mechanism of action. Dual FLT3-ITD and CDK9 protein degradation resulted in the block of FLT3-ITD downstream signalling pathways, apoptosis activation and cell cycle arrest of FLT3-ITD AML cells. Moreover, transcriptional repression caused by CDK9 degradation significantly reduced expression of crucial genes involved in AML pathogenesis. The obtained results indicate the beneficial impact of simultaneous FLT3-ITD/CDK9 degradation for AML therapy.

Department of Experimental Biology Faculty of Science Palacký University Olomouc Šlechtitelů 27 78371 Olomouc Czech Republic

Department of Organic Chemistry Faculty of Science Palacký University Olomouc 17 Listopadu 12 77146 Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Olomouc Hněvotínská 5 77900 Olomouc Czech Republic

Citace poskytuje Crossref.org