Styrylquinazoline derivatives as ABL inhibitors selective for different DFG orientations

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:

• Quinazoline
• kinase inhibitor
• tyrosine kinase
• ABL kinase
• leukaemia
• anticancer activity

Acknowledgements

We thank M.Sc. Michal Kuczak for technical assistance with cytotoxicity assays.

Author contributions

KM created the research hypothesis, designed, performed and analysed all of the biological experiments, wrote the manuscript; JM created the research hypothesis, designed the compounds, performed the chemical syntheses, analysed and discussed the in silico results; MP performed the molecular docking studies; RM reviewed and edited the manuscript. All of the authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

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].