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α-Triazolylboronic Acids: A Novel Scaffold to Target FLT3 in AML
Maria Luisa Introvigne1, Lorenza Destro2, Luca Mologni3
1Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
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 α-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.
Insights
Novel alpha-triazolylboronic acids show promise for treating acute myeloid leukemia (AML) by inhibiting FMS-like tyrosine kinase-3 (FLT3). These compounds offer a new therapeutic avenue, addressing challenges posed by drug resistance in AML treatment.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- Acute myeloid leukemia (AML) treatment is challenging due to drug resistance.
- FMS-like tyrosine kinase-3 (FLT3) mutations are key targets, but current therapies have limited success.
- Boronic acids can improve drug bioavailability and pharmacokinetics.
Purpose of the Study:
- To identify novel chemotypes for FLT3 inhibition in AML.
- To explore the potential of alpha-triazolylboronic acids as FLT3 inhibitors.
- To investigate the role of the boronic acid group in FLT3 inhibition.
Main Methods:
- Screening of in-house boronic acid library.
- Enzymatic and cellular assays for activity and selectivity.
- In-silico studies for binding mode analysis.
- Synthesis and testing of control analogues lacking the boronic acid group.
Main Results:
- Identification of alpha-triazolylboronic acids as a novel FLT3-targeting chemotype.
- Compounds demonstrated low micromolar activity in enzymatic and cellular assays.
- Selective inhibition against control cell lines was observed.
- In-silico studies revealed a consistent binding mode, with the boronic acid group being essential for activity.
Conclusions:
- Alpha-triazolylboronic acids represent a promising new class of compounds for FLT3 inhibition.
- This chemotype offers a potential strategy to overcome drug resistance in AML.
- Further development of these compounds could lead to improved AML therapies.
