Computer‐Guided Design, Synthesis, and Biological Evaluation of Quinoxalinebisarylureas as FLT3 Inhibitors

Abstract

Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in ∼30 % of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Point mutations in the tyrosine kinase domain (TKD) are observed as primary mutations or are acquired as secondary mutations in FLT3 with internal tandem duplications (ITDs) after treatment with tyrosine kinase inhibitors (TKIs). Although dozens of potent inhibitors against FLT3 ITD have been reported, activating TKD point mutations, especially at residues F691 and D835, remain the leading cause for therapy resistance, highlighting the consistent need for new potent inhibitors. Herein we report the identification and characterization of novel quinoxaline-based FLT3 inhibitors. We used the pharmacophore features of diverse known inhibitors as a starting point for a new optimization algorithm for type II TKIs, starting from an in silico library pharmacophore search and induced-fit docking in the known FLT3 structure. This led to the design of a set of diverse quinoxalinebisarylureas, which were profiled in an FLT3 kinase activity assay. The most promising compounds were further evaluated in a zebrafish embryo phenotype assay.

Copper catalyzed photoredox synthesis of α-keto esters, quinoxaline, and naphthoquinone: controlled oxidation of terminal alkynes to glyoxals

“…of 4,5-dimethylbenzene-1,2-diamine ( 7 ) to the reaction solution and irradiated it with visible light for 12 h at room temperature ( Scheme 3 ). Not surprisingly, we obtained the corresponding 6,7-dimethyl-2-phenylquinoxaline ( 8 ), which is a biologically active FLT3 inhibitor, 15 in 65% yield as a product in this unprecedented photoredox copper catalyzed one-pot process ( Scheme 3 ). We did not observe the formation of 3-phenylquinoxalin-2-ol as a product in the current photoredox method, which was previously reported as a key product under strong basic conditions.…”

Quinoxaline‐Based Scaffolds Targeting Tyrosine Kinases and Their Potential Anticancer Activity

“…It is the most common mutated gene in AML (was cloned in 1993 ) and has been expressed in most tissues including hematopoietic organs (spleen and bone marrow), prostate, ovary, heart, lung, kidney, and placenta . FLT3 structure is composed of an N‐terminal extracellular ligand binding domain with five immunoglobulin‐like motifs, a transmembrane domain followed by an intracellular juxta‐membrane domain, and a C‐terminal tyrosine kinase domain .…”

“…In 2009, Chao et al identified bisarylurea and they were evaluated as a uniquely potent and selective FLT3 inhibitor. In 2015, Göring et al designed a set of diverse quinoxaline‐bisarylureas, which were profiled in an FLT3 kinase activity assay. Their study used the pharmacophore features of different known inhibitors as a starting point for a new optimization algorithm for type II TKIs, starting from an in silico library pharmacophore search and induced‐fit docking in the known FLT3 structure.…”

“…Future studies will focus on the development of quinoxaline‐based inhibitors of the active kinase state to overcome increasing resistance to type II inhibitors caused by the FLT3 D835Y mutation .…”

Solvent- and halide-free synthesis of pyridine-2-yl substituted ureas through facile C–H functionalization of pyridine N-oxides

“…Ureas, especially those functionalized with a heterocyclic moiety, are widely applied in drug design 1,2 and demonstrate antimicrobial, 3,4 antimalarial, [5][6][7] antivirus, 8 and anticancer [9][10][11][12][13][14] activities. Moreover, ureas act as kinase (LIM, VEGFR2, FGFR, FLT3) inhibitors, [15][16][17][18][19][20] they control gastric acid secretion, 21 and are used as plant growth regulators. 22,23 All known syntheses of ureas employ either various organic (in particular, chlorinated) solvents or heavy metals.…”