Small molecule kinase inhibitors
Head: Vladimír Kryštof
Olomouc node
HOME INSTITUTION
Faculty of Medicine PU in Olomouc
RESEARCH PROGRAMME(S)
RP 2 - Research and development of anticancer pharmaceuticals and therapeutic methods
- Mission: Protein kinases and other therapeutic targets.
- Vision: Development of small molecule modulators of oncogenic kinases.
The group specializes in the development of protein kinase inhibitors with potential use in anti-cancer therapy. Our work involves the design, synthesis and investigation of compounds based on various heterocyclic systems. We have identified less common heterocycles as promising central motifs for the development of novel inhibitors. We focus not only on traditional competitive inhibitors, but also on innovative approaches such as modulation of the stability of target kinases via PROTAC-based technologies and molecular glues. Among the enzymes studied are mainly cyclin-dependent kinases, the receptor kinases FLT3 and PDGFR. Recently, we have been paying attention to less explored enzymes from the dark kinome.
SELECTED PUBLICATIONS
- Břehová P, Řezníčková E, Škach K, Jorda R, Dejmek M, Vojáčková V, Šála M, Kovalová M, Dračínský M, Dolníková A, Strmeň T, Kinnertová M, Chalupský K, Dvořáková A, Gucký T, Mertlíková Kaiserová H, Klener P, Nencka R, Kryštof V. Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2- b]pyridazine Derivatives Identified by Scaffold Hopping. J Med Chem. 2023 Aug 24;66(16):11133-11157. DOI: 10.1021/acs.jmedchem.3c00575
- Kovalová M, Havlíček L, Djukic S, Škerlová J, Peřina M, Pospíšil T, Řezníčková E, Řezáčová P, Jorda V, Kryštof V. Characterization of new highly selective pyrazolo[4,3-d]pyrimidine inhibitor of CDK7. Biomed Pharmacother. 2023 May;161:114492. DOI: 10.1016/j.biopha.2023.114492
- Jorda R, Havlíček L, Peřina M, Vojáčková V, Pospíšil T, Djukic S, Škerlová J, Grúz J, Renešová N, Klener P, Řezáčová P, Strnad M, Kryštof V. 3,5,7-Substituted Pyrazolo[4,3-d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders. J Med Chem. 2022 Jul 14;65(13):8881-8896. DOI: 10.1021/acs.jmedchem.1c02184
- Řezníčková E, Krajčovičová S, Peřina M, Kovalová M, Soural M, Kryštof V.. Modulation of FLT3-ITD and CDK9 in acute myeloid leukaemia cells by novel proteolysis targeting chimera (PROTAC). Eur J Med Chem. 2022 Sep 26;243:114792. DOI: 10.1016/j.ejmech.2022.114792
- Dayal N, Řezníčková E, Hernandez DE, Peřina M, Torregrosa-Allen S, Elzey BD, Škerlová J, Ajani H, Djukic S, Vojáčková V, Lepšík M, Řezáčová P, Kryštof V, Jorda R, Sintim HO. 3H-Pyrazolo[4,3-f]quinoline-Based Kinase Inhibitors Inhibit the Proliferation of Acute Myeloid Leukemia Cells In Vivo. J Med Chem. 2021 Aug 12;64(15):10981-10996. DOI: 10.1021/acs.jmedchem.1c00330
COLLABORATION WITHIN THE NICR
Michal Hocek
(Prague node, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences)
Pavel Klener
(Prague node, First Faculty of Medicine CU)
Pavlína Maloy Řezáčová
(Prague node, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences)
SPECIALIZED EXPERTISE AND TECHNOLOGY
Rational design of molecularly targeted compounds
Biochemical profiling of kinase inhibitors
Live cell microscopy, flow cytometry
COLLABORATION WITH LARGE RESEARCH INFRASTRUCTURES AND RESEARCH CENTRES
Central European Institute of Technology at Masaryk University CEITEC MU
National infrastructure for biological and biomedical imaging Czech-Bioimaging