Abstract C154: Investigation of indole-based molecules as a new class of TLK1 inhibitors in prostate cancer therapy

Abstract

Abstract Targeting protein kinases is an attractive strategy in cancer therapy owing to their importance in cell signaling pathways. Tousled-like kinases (TLKs) are associated with chromosomal integrity, DNA replication, and repair. However, the dysregulation of these genes can give rise to different aberrations. The activity of TLK1, a human isoform of TLK, is found to be attenuated in the case of prostate cancer and breast cancer, as it can phosphorylate many proteins of the DNA Damage Response (DDR) pathway, hence making TLK1 a novel druggable target. To date, phenothiazines-which are known antipsychotic drugs, are the only class of inhibitors reported against TLK1. Our work focuses on developing a new class of TLK1 inhibitors to broaden the spectrum of understanding TLK1 inhibition. As an approach, we designed, synthesized, and validated indole-based molecules with potent TLK1 inhibition via in-silico studies. We further explored the synthesized inhibitors to understand their inhibition against recombinantly purified TLK1 in the presence of its different substrates. Also, the cell viability of these inhibitors was examined against breast cancer and prostate cancer. We found that the inhibitors are more potent in prostate cancer cell lines, as observed by the lowered downstream phosphorylation levels of TLK1 substrates in those cells. The in-vitro, cell, and docking studies imply that the newly designed inhibitors have better potency against TLK1 than its reported inhibitors. We anticipate that our step towards exploring a new class of potent TLK1 inhibitors would aid in elevating the therapeutics in a combinatorial approach to existing prostate cancer therapy. References: 1. Cohen, P., Cross, D. and Jänne, P.A. Kinase drug discovery 20 years after imatinib: progress and future directions. 2021, Nat Rev Drug Discov 20, 551–569. 2. Kirubakaran, S; Thiruvenkatam, V; and George, J. "An indole-based kinase inhibitor and a process for its preparation", Indian Patent Office, Patent Application No.: 202121048608, 2021, Oct. 25. 3. Johnson, D., J. Hussain, S. Bhoir, V. Chandrasekaran, P. Sahrawat, T. Hans, M. I. Khalil, A. De Benedetti, V. Thiruvenkatam, and S. Kirubakaran. Synthesis, kinetics and cellular studies of new phenothiazine analogs as potent human-TLK inhibitors. 2023, Org. Biomol. Chem, Advance article, 10.1039/D2OB02191A. 4. Singh, V., Bhoir, S., Chikhale, R.V., Hussain, J., Dwyer, D., Bryce, R.A., Kirubakran, S. and De Benedetti, A. Generation of Phenothiazine with Potent Anti-TLK1 Activity for Prostate Cancer Therapy. 2020, Iscience, 23, 101474. Citation Format: Delna Johnson, Sivapriya Kirubakaran, Vijay Thiruvenkatam. Investigation of indole-based molecules as a new class of TLK1 inhibitors in prostate cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C154.