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Article Abstract
We report the optimization of a series of IRAK1/4/pan-FLT3 kinase inhibitors. These efforts have produced a key compound that displays potent and selective inhibition of IRAK1, IRAK4, and FLT3, reduced block of hERG, and good pharmacokinetic properties. In a mouse xenograft model of acute myeloid leukemia (AML), produces survival prolongation superior to that of gilteritinib, the leading FDA-approved FLT3 inhibitor currently used to treat AML.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067127 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.5c00147 | DOI Listing |
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Optimization of IRAK1/4/pan-FLT3 kinase inhibitors as treatments for acute myeloid leukemia.
Bioorg Med Chem Lett
August 2025
National Center for Advancing Translational Sciences, Rockville, MD 20850, United States. Electronic address:
FLT3 kinase inhibitors have been advanced to the clinic as targeted treatments for acute myeloid leukemia (AML). These inhibitors can produce promising initial responses, but patients often relapse with treatment-resistant disease. A significant factor contributing to relapse involves adaptive signaling through an alternative pathway mediated by IRAK1 and IRAK4 kinases.
View Article and Find Full Text PDFIRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia.
ACS Med Chem Lett
May 2025
National Center for Advancing Translational Sciences, Rockville, Maryland 20850, United States.
We report the optimization of a series of IRAK1/4/pan-FLT3 kinase inhibitors. These efforts have produced a key compound that displays potent and selective inhibition of IRAK1, IRAK4, and FLT3, reduced block of hERG, and good pharmacokinetic properties. In a mouse xenograft model of acute myeloid leukemia (AML), produces survival prolongation superior to that of gilteritinib, the leading FDA-approved FLT3 inhibitor currently used to treat AML.
View Article and Find Full Text PDFDiscovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia.
ACS Med Chem Lett
November 2024
National Center for Advancing Translational Sciences, Rockville, Maryland 20850, United States.
We report the discovery of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization of this series has produced compound which displays potent and selective inhibition of IRAK1, IRAK4, FLT3, and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.
View Article and Find Full Text PDF