2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2022 May 5;235:114292. doi: 10.1016/j.ejmech.2022.114292.
Vincenzo Cilibrasi 1,  Virginia Spanò 1,  Roberta Bortolozzi 2,  Marilia Barreca 1,  Maria Valeria Raimondi 1,  Roberta Rocca 3,  Annalisa Maruca 4,  Alessandra Montalbano 5,  Stefano Alcaro 6,  Roberto Ronca 7,  Giampietro Viola 8,  Paola Barraja 1
Affiliations

Affiliations

  • 1 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy.
  • 2 Istituto di Ricerca Pediatrica IRP, Fondazione Città della Speranza, Corso Stati Uniti 4, 35127, Padova, Italy.
  • 3 Net4Science srl, Academic Spinoff, Università Magna Græcia di Catanzaro, Viale Europa, 88100, Catanzaro, Italy; Dipartimento di Medicina Sperimentale e Clinica, Università Magna Græcia di Catanzaro, Viale Europa, 88100, Catanzaro, Italy.
  • 4 Dipartimento di Scienze della Salute, Università Magna Græcia di Catanzaro, Viale Europa, 88100, Catanzaro, Italy; Net4Science srl, Academic Spinoff, Università Magna Græcia di Catanzaro, Viale Europa, 88100, Catanzaro, Italy.
  • 5 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy. Electronic address: alessandra.montalbano@unipa.it.
  • 6 Net4Science srl, Academic Spinoff, Università Magna Græcia di Catanzaro, Viale Europa, 88100, Catanzaro, Italy; Dipartimento di Scienze della Salute, Università Magna Græcia di Catanzaro, Viale Europa, 88100, Catanzaro, Italy. Electronic address: alcaro@unicz.it.
  • 7 Dipartimento di Medicina Molecolare e Traslazionale Unità di Oncologia Sperimentale ed Immunologia, Università di Brescia, 25123, Brescia, Italy.
  • 8 Istituto di Ricerca Pediatrica IRP, Fondazione Città della Speranza, Corso Stati Uniti 4, 35127, Padova, Italy; Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia Università di Padova, Via Giustiniani 2, 35131, Padova, Italy. Electronic address: giampietro.viola.1@unipd.it.
PMID: 35339838 DOI: 10.1016/j.ejmech.2022.114292
Abstract

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.

Keywords

2H-imidazo [2′,1':2,3][1,3]thiazolo[4,5-e]isoindol-8-yl-phenylureas; Acute myeloid leukemia (AML); FLT3/ITD; FMS-like tyrosine kinase 3 (FLT3); Internal tandem duplication (ITD).

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