Natural and Semisynthetic Chalcones as Dual FLT3 and Microtubule Polymerization Inhibitors.
Haleema Sadia MalikAishah BilalRahim UllahMaheen IqbalSardraz KhanIshtiaq AhmedKarsten KrohnRahman Shah Zaib SaleemHidayat HussianAmir FaisalPublished in: Journal of natural products (2020)
Activating mutations in FLT3 receptor tyrosine kinase are found in a third of acute myeloid leukemia (AML) patients and are associated with disease relapse and a poor prognosis. The majority of these mutations are internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3, which have been validated as a therapeutic target. The clinical success of selective inhibitors targeting oncogenic FLT3, however, has been limited due to the acquisition of drug resistance. Herein the identification of a dual FLT3/microtubule polymerization inhibitor, chalcone 4 (2'-allyloxy-4,4'-dimethoxychalcone), is reported through screening of 15 related chalcones for differential antiproliferative activity in leukemia cell lines dependent on FLT3-ITD (MV-4-11) or BCR-ABL (K562) oncogenes and by subsequent screening for mitotic inducers in the HCT116 cell line. Three natural chalcones (1-3) were found to be differentially more potent toward the MV-4-11 (FLT3-ITD) cell line compared to the K562 (BCR-ABL) cell line. Notably, the new semisynthetic chalcone 4, which is a 2'-O-allyl analogue of the natural chalcone 3, was found to be more potent toward the FLT3-ITD+ cell line and inhibited FLT3 signaling in FLT3-dependent cells. An in vitro kinase assay confirmed that chalcone 4 directly inhibited FLT3. Moreover, chalcone 4 induced mitotic arrest in these cells and inhibited tubulin polymerization in both cellular and biochemical assays. Treatment of MV-4-11 cells with this inhibitor for 24 and 48 h resulted in apoptotic cell death. Finally, chalcone 4 was able to overcome TKD mutation-mediated acquired resistance to FLT3 inhibitors in a MOLM-13 cell line expressing FLT3-ITD with the D835Y mutation. Chalcone 4 is, therefore, a promising lead for the discovery of dual-target FLT3 inhibitors.
Keyphrases
- acute myeloid leukemia
- tyrosine kinase
- allogeneic hematopoietic stem cell transplantation
- cell death
- epidermal growth factor receptor
- poor prognosis
- cell cycle arrest
- induced apoptosis
- high throughput
- long non coding rna
- cell cycle
- end stage renal disease
- signaling pathway
- newly diagnosed
- prognostic factors
- chronic kidney disease
- peritoneal dialysis
- anti inflammatory
- single cell
- binding protein