Development and comparison of single FLT3-inhibitors to dual FLT3/TAF1-inhibitors as an anti-leukemic approach.

Abstract

Acute myeloid leukemia (AML) is characterized by several recurrent mutations that affect disease biology and phenotype, response to therapy and risk of subsequent relapse. Though tyrosine kinase inhibitors have gained regulatory approval for the treatment of AML, it is unclear whether single drugs targeting a specific genomic alteration will be sufficient to eradicate disease. Fortuitously, kinase/bromodomain inhibitors allow targeting of downstream transcriptional effectors of oncogenic pathways, allowing impediment of drug resistance at the transcriptional level. Successful development of combinatorial therapeutic strategies to inhibit both upstream oncogenic pathways and their downstream effectors could thus impede the onset of resistant disease. By using a combination of high-throughput cell-based screening assays and structure-based design, we have developed a novel anti-proliferative 3i-compound scaffold with a diverse range of single and dual FLT3/TAF1(2) activity against AML. Our novel approach to target both FLT3 kinase and TAF1(2) bromodomain efficiently maintained potency against haematological cancers. However, reference compounds and in vitro cell viability and cytotoxicity assays in cancer cell lines demonstrated superior effects of high affinity tyrosine kinase inhibition compared to inhibition of the TAF1 bromodomain. Our results highlight the feasibility of dual tyrosine kinase-bromodomain targeting to overcome disease mechanisms while also revealing the increased efficacy of FLT3-targeted compounds in AML.