Introduction

The present invention relates to compounds able to cause FLT3 inhibition and apoptosis in MOLM-13 and MV4-11 leukaemic cells at IC50 values in the nanomolar range. In vivo, one of the derivatives reduces tumour growth at a dose between 1 and 3 mg/Kg without apparent toxic effects. If properly developed, our compounds could represent a promising approach in the treatment of AML.

Technical features

Acute myeloid leukaemia (AML) is an aggressive haematological cancer often associated with mutation of the FMS-like Tyrosine Kinase 3 (FLT3) gene, which is involved in the regulation of cell proliferation processes. Internal Tandem Duplication (ITD), one of the most common mutations, is associated with a high recurrence rate and low therapetic response. The present invention relates to compounds able to cause cell cycle block in G1, apoptosis in MOLM-13 and MV4-11 cells expressing the constitutively activated mutant FLT3/ITD, with IC50 values between 11 and 14 nM and inhibition of FLT3 phosphorylation (IC50 between 1.4 and 6.7 nM). In vivo, one candidate reduces tumour growth at a dose between 1 and 3 nM with no apparent toxic effects. A study of the ADMET/PK profile would drive the lead optimisation process necessary for an adequate development of our derivatives as promising compounds in the treatment of AML.

Possible Applications

• Development of new chemotherapeutics for the treatment of AML;
• Combination therapy with kinase inhibitors to overcome AML.

Advantages

• Versatile synthetic approach;
• High antiproliferative activity in MOLM-13 and MV4-11 cells;
• Significant inhibition of FLT3 phosphorilation;
• Relevant preclinic study with no apparent toxic effects.