Synthesis of 2H-Imidazo[2',1':2,3] [1,3]thiazolo[4,5-e]isoindol-8-yl-phenylureas with promising therapeutic features for the treatment of acute myeloid leukemia (AML) with FLT3/ITD mutations

Despite progressive advances in understanding the molecular biology of acute myeloid leukemia (AML), the conventional therapeutic approach has not changed substantially, and the outcome for most patients is poor. Thus, continuous efforts on the discovery of new compounds with improved features are required. Following a multistep sequence, we have identified a new tetracyclic ring system with strong antiproliferative activity towards several haematological cell lines. The new compounds possess structural properties typical of inactive-state-binding kinase inhibitors and are structurally related to quizartinib which is known as type-II tyrosine kinase inhibitor. In particular, the high activity found in two cell lines MOLM-13 and MV4-11, expressing the constitutively activated mutant FLT3/ITD, indicates inhibition of FLT3 kinase and on the basis of structure-activity relationship (SAR) the presence of an ureido moiety demonstrates to play a key role in driving the antiproliferative activity towards these cell lines. Molecular modelling studies supported the mechanism of recognition of the most active compounds within the FLT3 pocket where quizartinib binds. Moreover, Molecular Dynamics simulation (MDs) revealed the formation of a recurrent H-bond with Asp829, which more stabilizes the complex of 9c and the FLT3 inactive state. In MV4-11 cell line compound 9c reduces the phosphorylation of FLT3 (Y591) and some of its downstream targets leading to cell cycle arrest at G1 phase and induction of apoptosis. In an MV4-11 xenograft mouse model, 9c significantly reduces the tumor growth at the dose of 1-3 mg/kg without apparent toxicity.

Automated summary

A new tetracyclic ring system with strong antiproliferative activity towards several haematological cell lines has been identified through a multistep sequence. These compounds exhibit high activity in cell lines expressing the mutant FLT3/ITD, potentially inhibiting FLT3 kinase. Molecular modelling and Molecular Dynamics simulation support the mechanism of action, with compound 9c reducing phosphorylation of FLT3 and downstream targets, leading to cell cycle arrest and apoptosis. In a mouse model, compound 9c significantly reduces tumor growth without obvious toxicity.