Identification of Furo[2,3-D]Pyrimidin-4-Ylsulfanyl-1,3,4-Thiadiazole Derivatives As Novel Flt3-Itd Inhibitors Publisher Pubmed

Summary: AML breakthrough? Study synthesizes furo[2,3-d]pyrimidines, 49 inhibits FLT3-ITD (nM range), STAT5/ERK. Research suggests type II binders for resistance. Cure edge? #AcuteMyeloidLeukemia #FLT3Inhibitors

Moradi M^{1, 2} ; Mousavi A^{1, 2} ; Reznickova E³ ; Peytam F⁴ ; Perina M³ ; Vojackova V³ ; Firoozpour L² ; Jorda R³ ; Gruz J³ ; Emamgholipour Z² ; Sadatebrahimi SE² ; Krystof V^{3, 5} ; Foroumadi A^{2, 4}
Source: European Journal of Medicinal Chemistry Published:2024

Abstract

Given the significant prevalence of FLT3 receptor and its mutations in acute myeloid leukemia (AML) pathogenesis, we present a novel series of furo[2,3-d]pyrimidin-1,3,4-thiadiazole-urea derivatives, designed to exhibit FLT3-ITD inhibitory activity. These compounds demonstrated cytotoxicity in FLT3-ITD expressing AML cell lines MOLM-13 and MV4-11 in the nanomolar range, with significant selectivity over the K562 cell line. In-depth evaluations of example compound 49 revealed its efficacy in suppressing FLT3 phosphorylation and the downstream signaling molecules, including STAT5 and ERK1/2. Notably, compound 49 demonstrated cytotoxic effects in Ba/F3 cells expressing FLT3-ITD or FLT3-ITD-F691L mutant, exceeding the potency of both sorafenib and quizartinib. Molecular docking studies suggest that this compound binds to the active site of FLT3 in a type II manner. The study suggests that substituted furo[2,3-d]pyrimidines could be useful additions to the growing field of FLT3-targeted therapy for AML. These compounds have the potential to serve as novel FLT3-ITD inhibitors and may offer insights for developing future therapeutic strategies in AML. © 2024 The Authors