Indole-based FLT3 inhibitors and related scaffolds as potential therapeutic agents for acute myeloid leukemia

Abstract

Fms-like tyrosine kinase 3 (FLT3) mutation mechanisms are among the most common genetic abnormalities detected in about 30% of acute myeloid leukemia (AML) patients. These mutations are accompanied by poor clinical response, although all these progressions in identifying and interpreting biological AML bio-targets. Several small structured FLT3 inhibitors have been ameliorated to struggle against AML. Despite all these developments regarding these inhibitors, the Overall survival rate is about five years or more in less than one-third of diagnosed AML patients. Midostaurin was the first FDA-approved FLT3 inhibitor in 2017 in the United States and Europe for AML remedy. Next, Gilteritinib was an FDA-approved FLT3 inhibitor in 2018 and in the next year, Quizartinib was approved an as FLT3 inhibitor in Japan. Interestingly, indole-based motifs had risen as advantaged scaffolds with unusual multiple kinase inhibitory activity. This review summarises indole-based FLT3 inhibitors and related scaffolds, including FDA-approved drugs, clinical candidates, and other bioactive compounds. Furthermore, their chemotypes, mechanism of action, and interaction mode over both wild and mutated FLT3 target proteins had been judgmentally discussed. Therefore, this review could offer inspiring future perspectives into the finding of new FLT3-related AML therapies.

AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

“…Concerning the mechanism of binding to the FLT3 kinase domain as an FLT3 type 1 inhibitor, gilteritinib acts as an ATP-competitive agent by interacting with DFG-in conformation of FLT3-TKD and forming two hydrogen bonds with amino acids Cys694 and Glu692. However, gilteritinib also shows some other interactions, especially with the gatekeeper residue F691, which is presumed to be one of the leading reasons for gilteritinib resistance, as enzymatically confirmed [77].…”

Fucoidan’s Molecular Targets: A Comprehensive Review of Its Unique and Multiple Targets Accounting for Promising Bioactivities Supported by In Silico Studies

“…Heparan sulphate chains in extracellular matrixes and cellular membranes are broken down by the enzyme heparanase (HPSE), which influences cell adhesion, migration, invasion, and tissue integrity. As a result, HPSE activity is dysregulated, making it a desirable target for anti-inflammatory, antiangiogenic, and antimetastatic drugs [200]. Sulphated polysaccharides and oligosaccharides have been suggested as potential HPSE Heparan sulphate chains in extracellular matrixes and cellular membranes are broken down by the enzyme heparanase (HPSE), which influences cell adhesion, migration, invasion, and tissue integrity.…”

“…Sulphated polysaccharides and oligosaccharides have been suggested as potential HPSE Heparan sulphate chains in extracellular matrixes and cellular membranes are broken down by the enzyme heparanase (HPSE), which influences cell adhesion, migration, invasion, and tissue integrity. As a result, HPSE activity is dysregulated, making it a desirable target for anti-inflammatory, antiangiogenic, and antimetastatic drugs [200]. Sulphated polysaccharides and oligosaccharides have been suggested as potential HPSE inhibitors, while the residues Glu343 and Glu225 have previously been identified as HPSE proton donors and nucleophiles [201,202].…”

“…The 3D X-ray structures of proteins, including TLR4, TNFR, CLEC-2, PIK3, FLT3, HPSE, and HK IV, were obtained from the Protein Data Bank (PDB ID: 3FXI [181], 1EXT [208], 2C6U [209], 3DBS [210], 6JQR [196], 5E9C [200], and 3F9M [211], respectively, accessed on 1 October 2023). These proteins were obtained when water and co-crystallization molecules were removed before hydrogen bonds were added to minimize energy use using Chimera 1.16 software.…”

Discovery and Anticancer Screening of Novel Oxindole-Based Derivative Bearing Pyridyl Group as Potent and Selective Dual FLT3/CDK2 Kinase Inhibitor

“…This leads to autophosphorylation and the subsequent activation of downstream signaling cascades, including RAS/MEK, PI3K/AKT/mTOR, and JAK/STAT [14]. These pathways have crucial functions in controlling the cell cycle, cell death, and cell specialization [15]. Cyclin-dependent kinases (CDKs) are another type of protein kinases that specifically phosphorylate serine and threonine residues.…”