Natural and Semisynthetic Chalcones as Dual FLT3 and Microtubule Polymerization Inhibitors

Abstract

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.

Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy

“…Malik et al 163 identified a dual tubulin−FMS-like tyrosine kinase 3 (FLT3) chalcone 73 (Figure 17C). It reduced phosphorylation of two key downstream targets of FLT3, namely, signal transducer and activator of transcription 5 (Stat5) and/or extracellular signal-regulated kinase (ERK), which is consistent with the antiproliferative activity toward FLT3-internal tandem duplications (ITDs) mutation cell lines MV-4−11 (IC 50 = 0.24 μM) and MOLM-13 (IC 50 = 0.20 μM).…”

Two Important Anticancer Mechanisms of Natural and Synthetic Chalcones

“…The compound forms two hydrogen bonds with tubulin on Leu255 and Cys241 residues. The phenyl residue adjacent to the carbonyl group forms Π-σ interactions with Leu248, and the other aromatic residue interacts with residues Ala180 and Lys254 [ 224 ].…”

Identification and Characterization of Natural and Semisynthetic Quinones as Aurora Kinase Inhibitors

“…Please see ref for instrumentation. Naphthazarin ( 1 ); isoplumbagin ( 2 ); , 3-chlorojuglone ( 3 ); , juglone ( 4 ); , 2-bromo-3-methyl-1,4-naphtho-quinone ( 5 ); 6-methoxynaphthoquinone ( 6 ); , 2-butenoic acid, 4-[1,4-dihydro-3-[4-(2-methyl-1,3-dioxolan-2-yl)-3-oxobutyl]-1,4-dioxo-2-naphthalenyl]-3-methoxy-, methyl ester ( 8 ); 2-(2-buten-1-yl)-3-hydroxy-1,4-naphthoquinone ( 9 ); β-lapachone ( 10 ); , and 2-(chloromethyl)­quinizarin ( 11 ) were prepared and characterized following procedures reported in the literature.…”