Denisa Sarova
PC33 – Denisa Sarova
Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Czechia
Biomedical Research Centre, University Hospital Hradec Kralove, Hradec Kralove, Czechia
ORCID
sarovad@faf.cuni.cz
| Discovery of Novel FLT3-Tyrosine Kinase Inhibitors for the Treatment of Acute Myeloid Leukemia |
| Sarova Denisa1,2, Gorecki Lukas2, Krystof Vladimir3, Rezacova Martina4, Ceckova Martina5, Korabecny Jan2, and Kratky Martin1 1 Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 03 Hradec Kralove, Czechia 2 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czechia 3 Laboratory of Growth Regulators, Palacky University and Institute of Experimental Botany, The Czech Academy of Sciences, Slechtitelu 27, 783 71 Olomouc, Czechia 4 Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Simkova 870, 500 03 Hradec Kralove, Czechia 5 Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 03 Hradec Kralove, Czechia |
| Abstract Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that continues to be associated with poor therapeutic outcomes. While conventional chemotherapy remains the cornerstone of AML treatment, increasing attention has been directed toward targeted therapies that exploit specific genetic abnormalities in leukemic cells. One of the most common oncogenic drivers in AML is the FLT3 internal tandem duplication (FLT3-ITD) mutation, which results in constitutive activation of the FLT3 receptor and drives uncontrolled cellular proliferation. Although FLT3 inhibitors such as midostaurin and gilteritinib have been approved for clinical use, their effectiveness is often limited by the development of drug resistance, highlighting the need for next-generation inhibitors with improved potency and resistance profiles.[1] To address this need, we identified a novel series of small-molecule FLT3 inhibitors based on our lead compound K1872. Structure-guided optimization generated several distinct compound series and produced several candidates with nanomolar activity against FLT3-ITD as well as strong antiproliferative effects in AML cell lines.[2] Notably, the most advanced compounds exhibited strong kinase selectivity relative to clinically established FLT3 inhibitors. Their antileukemic efficacy was further confirmed in primary leukemic blasts from AML patients, supporting the translational potential of this scaffold for the development of next-generation FLT3-targeted therapies. |
| References [1]Z. Wang et al., FLT3 Inhibitors in Acute Myeloid Leukemia: Challenges and Recent Developments in Overcoming Resistance, J. Med. Chem. 64 (2021) 2878–2900. https://doi.org/10.1021/acs.jmedchem.0c01851. [2] L. Gorecki et al., Strategies for the treatment of acute myeloid leukemia with FLT3 mutations: a patent review, Expert Opin. Ther. Pat. 35 (2025) 137–164. https://doi.org/10.1080/13543776.2024.2446224. This work has been supported by the project “Pre-application research of drugs for oncological diseases and for the prevention and treatment of serious complications caused by them (OncoPharm), project ID CZ.02.01.01/00/23_021/0008442”, co‑funded by the European Union |