Syntéza inhibitorů FLT3 kinázy pro terapii akutní myeloidní leukémie

Sudický, Patrik Marián

Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry in collaboration with Biomedical Research Center UH HK Author: Patrik Marián Sudický Supervisor: PharmD. Lukáš Opálka, Ph.D. Advisor: PharmD. Lukáš Górecki, Ph.D. Title of diploma thesis: Synthesis of FLT3 kinase inhibitors for the treatment of acute myeloid leukemia Acute myeloid leukemia (AML) is a heterogeneous malignancy arising from abnormal clonal expansion of myeloid hematopoietic precursors. Despite the low curability rates, with an average 5-year survival rate of 30%, recent scientific research has identified many genetic aberrations that have brought new chances for the patients. This work focuses on a key mutation occurring in 30% of AML patients, which is the mutation of FMS-like tyrosine kinase receptor-3 (FLT3) kinase. Although several FLT3 inhibitors have already been developed and approved for clinical use (midostaurin in 2017, and gilteritinib in 2018), primary and secondary resistance is limiting their efficacy. Therefore, the aim of this work is to develop and test new small molecules that would inhibit FLT3 by targeting other binding sites that might be less susceptible to point mutations leading to resistance compared to the clinically used drugs. The work arises from a hit...

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