Abstract:
Androgen deprivation therapy (ADT) is currently the primary treatment regime for Prostate cancer patients for advanced and local tumors. However, 70 % of the patients develop resistance to ADT due to various underlying mechanisms over the years. Researchers have identified the involvement of Tousled-like kinase 1 (TLK1) as a primary reason for ADT resistance and metastatic tumor development, representing TLK1 as an effective druggable target for prostate cancer. To date, phenothiazines-which are known antipsychotic drugs, are the only class of inhibitors reported against TLK1. In this study, we focus on developing a new class of TLK1 inhibitors to broaden the spectrum of understanding TLK1 inhibition. As an approach, we designed, synthesized, and validated pyridazinone-fused indole molecules with potent TLK1 inhibition with the concept of ligand-based drug discovery. The inhibition studies and biochemical assays identified a molecule 5n with better inhibition potential than reported J54. Also, the synthesized inhibitors are toxic to androgen-sensitive LNCaP prostate cancer cell lines in sub-micromolar levels and inhibit the TLK1 pathway in cells. Additionally, the combination of anti-androgens and 5n reduces the clonogenicity of cells, causes an accumulation of DNA damage, and induces apoptosis cell death in the LNCaP cells. We anticipate that our step towards exploring a new class of potent TLK1 inhibitors would aid in elevating the therapeutics to existing prostate cancer therapy and provide strong validation for future drug design for more potent and specific TLK1 inhibitors.