Discovery of a Novel Orally Bioavailable FLT3-PROTAC Degrader for Efficient Treatment of Acute Myeloid Leukemia and Overcoming Resistance of FLT3 Inhibitors.
Junwei WangQuanjin RongLei YeBingqian FangYifan ZhaoYu SunHaikun ZhouDan WangJinting HeZhenzhen CuiQijian ZhangDi KangLihong HuPublished in: Journal of medicinal chemistry (2024)
Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis-targeting chimeras (PROTACs) represent a promising approach to eliminate the resistance of FLT3 inhibitors. However, due to the poor druggability of PROTACs, the development of orally bioavailable FLT3-PROTACs faces great challenges. Herein, a novel orally bioavailable FLT3-ITD degrader A20 with excellent pharmacokinetic properties was discovered through reasonable design. A20 selectively inhibited the proliferation of FLT3-ITD mutant acute myeloid leukemia (AML) cells and potently induced FLT3-ITD degradation through the ubiquitin-proteasome system. Notably, oral administration of A20 resulted in complete tumor regression on subcutaneous AML xenograft models. Furthermore, on systemic AML xenograft models, A20 could completely eliminate the CD45 + CD33 + human leukemic cells in murine and significantly prolonged the survival time of mice. Most importantly, A20 exerted significantly improved antiproliferative activity against drug-resistant AML cells compared to existing FLT3 inhibitors. These findings suggested that A20 could serve as a promising drug candidate for relapsed or refractory AML.
Keyphrases
- acute myeloid leukemia
- allogeneic hematopoietic stem cell transplantation
- drug resistant
- induced apoptosis
- cell cycle arrest
- small molecule
- signaling pathway
- endothelial cells
- tyrosine kinase
- emergency department
- cell death
- metabolic syndrome
- pseudomonas aeruginosa
- high throughput
- adipose tissue
- high glucose
- drug induced
- skeletal muscle
- cell proliferation
- diabetic rats
- combination therapy
- multiple myeloma
- electronic health record