TASK-1 Inhibitors: Unraveling Potential Drug Leads
Click the Poster to View Full Screen, Right click to save image
Martha Julemis
CoPIs:
Ramish Zahed , Hinaben Patel, Youssef Elhowary, Gianna Kiszka, Sofiia Korotka, Erika Salgado, Diana Figueroa Chea, Oluwatoni Awoleye
College:
The Dorothy and George Hennings College of Science, Mathematics, and Technology
Major:
Biotechnology Science
Faculty Research Advisor(s):
Thomas Comollo
Abstract:
The TWIK-Related Acid-Sensitive Potassium Channel 1 (TASK-1) plays a crucial role in regulating and responding to changes in membrane potentials within a cell. Encoded by the KCNK3 gene, TASK-1 exists as a potassium channel with a two-pore domain structure, belonging to the K2P family. Situated on the external surface of the cell membrane in humans, TASK-1 channels control potassium ion flow across cell membranes. TASK-1 exhibits versatility across different tissues, ranging from the central nervous system to cardiovascular tissues. These channels contribute to the regulation of neuronal activity and neurotransmitter release while also influencing cardiac action potentials. In addition to modulating cell excitability, TASK-1 channels have also been shown to exhibit proapoptotic effects among certain populations of cancer cell lines. During this study, it was suggested that the inner vestibule of the TASK 1 channel serves as a binding site for established TASK inhibitors. This distinctive characteristic renders TASK-1 a promising target for inhibitor studies aimed at chemical regulation or drug intervention for future potential therapeutic implications. In our research, we propose to target the inner vestibule of the TASK-1 channels, a known binding site for TASK-1 inhibitors like BAY10000493 and BAY2341237, to identify new TASK-1 inhibitors. We conducted virtual screening and small molecule docking studies using approximately 900,000 compounds from the ZINC12 database. Initial results yielded a promising hit molecule, for which we named KU124, and was validated through a thallium flux assay using an inducible TASK-1-GFP expressing CHO cells line. Our findings suggest that the inner vestibule of the TASK-1 channels can be exploited to discover additional inhibitors and validate our virtual screening approach. Currently, we are focused on identifying drug-like small molecules predicted to inhibit TASK-1 channel conductance through in silico docking simulations and virtual screening. Furthermore, we aim to evaluate selected molecules in vitro assays to confirm their ability to inhibit TASK-1 channel conductance. Additionally, we intend to further investigate KU124 and other hit molecules in cancer cell viability assays to assess their potential as anti-cancer agents.