α- Triazolylboronic acids: a novel scaffold to target FLT3 in AML.

ABSTRACT

The treatment of acute myeloid leukemia (AML) presents a challenge to current therapies because of the development of drug resistance. Genetic mutation of FMS-like tyrosine kinase-3 (FLT3) is a target of interest for AML treatment, but the use of FLT3-targeting agents on AML patients has so far resulted in poor overall clinical outcomes.1 The incorporation of the boronic group in a drug scaffold could enhance the bioavailability and pharmacokinetic profile of conventional anticancer chemotypes. Boronic acids represent an intriguing and unexplored class of compounds in the context of AML, and they are only scantly reported as inhibitors of protein kinases. We identified a-triazolylboronic acids as a novel chemotype for targeting FLT3 by screening a library of structurally heterogeneous in-house boronic acids. Selected compounds show low micromolar activities on enzymatic and cellular assays, selectivity against control cell lines and a recurring binding mode in in-silico studies. Furthermore, control analogues synthesized ad hoc and lacking the boronic acid are inactive, confirming that this group is essential for the activity of the series. All together, these results suggest α-triazolylboronic acids could be a promising novel chemotype for FLT3 inhibition, laying the ground for the design of further compounds.