Tousled-like kinases are involved in maintaining the genomic integrity, cell cycle progression and cell repair. TLK genes have been upregulated in cancer cells, and the silencing of TLK expression has lead to suppression of cell growth. TLK1/TLK1B are found to phosphorylate specific substrates that are involved in the DNA damage response pathway, and hence increase the resistance of cells to ionizing radiation via a double strand break (DSB) repair. This makes TLK1B a therapeutic drug target against cancer therapy. Previously, we have characterized a potent phenothiazine analogue J54, with promising results during the in vivo studies. Recently, a few bis-indole derivatives were indentified to have inhibitory effect on the TLK1B, which is amplified especially in prostate cancer cells.
Our work focuses on the design, synthesis and biological evaluation of novel indole analogues which are modified with the structural features of J54, to improve the pharmacokinetic properties of the molecule. The synthesized compounds are having specific inhibition for the TLK1B which was assessed using in vitro kinase assay. Our results show that the molecules are having substrate specific inhibition when the phosphorylation is analyzed with three major interacting partners of TLK-Asf1a, Histone H3 and Nek1. Moreover, the in silico study of the analogues identifies improved interaction with the major catalytic site of the kinase in comparison with reported TLK inhibitors. Further, the compounds show enhanced solubility for biological studies, which was a major drawback of J54. To sum up, we identified novel class of indole analogues as potent anticancer agents that can inhibit TLK activity.

Graphical Abstract

Delna Johnson

Appearances