Styrylquinazoline derivatives as ABL inhibitors selective for different DFG orientations

Katarzyna Malarz; Jacek Mularski; Marcin Pacholczyk; Robert Musiol

doi:10.1080/14756366.2023.2201410

Styrylquinazoline derivatives as ABL inhibitors selective for different DFG orientations

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2201410. doi: 10.1080/14756366.2023.2201410.

Authors

Katarzyna Malarz¹, Jacek Mularski², Marcin Pacholczyk³, Robert Musiol²

Affiliations

¹ Institute of Physics, University of Silesia in Katowice, Chorzów, Poland.
² Institute of Chemistry, University of Silesia in Katowice, Chorzów, Poland.
³ Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland.

Abstract

Among tyrosine kinase inhibitors, quinazoline-based compounds represent a large and well-known group of multi-target agents. Our previous studies have shown interesting kinases inhibition activity for a series of 4-aminostyrylquinazolines based on the CP-31398 scaffold. Here, we synthesised a new series of styrylquinazolines with a thioaryl moiety in the C4 position and evaluated in detail their biological activity. Our results showed high inhibition potential against non-receptor tyrosine kinases for several compounds. Molecular docking studies showed differential binding to the DFG conformational states of ABL kinase for two derivatives. The compounds showed sub-micromolar activity against leukaemia. Finally, in-depth cellular studies revealed the full landscape of the mechanism of action of the most active compounds. We conclude that S⁴-substituted styrylquinazolines can be considered as a promising scaffold for the development of multi-kinase inhibitors targeting a desired binding mode to kinases as effective anticancer drugs.

Keywords: ABL kinase; Quinazoline; anticancer activity; kinase inhibitor; leukaemia; tyrosine kinase.

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Molecular Docking Simulation
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Quinazolines / pharmacology

Substances

styrylquinazoline
Protein Kinase Inhibitors
Antineoplastic Agents
Quinazolines

Grants and funding

This study was supported by National Science Centre grants [2019/35/B/NZ5/04208] (K.M.). The chemical part was also partially financed from National Science Centre grant [2018/31/B/NZ7/02122] (R.M.). Molecular docking software and computational resources were financed from Silesian University of Technology statutory funds [02/040/BK_22/1022].