Abstract P69: Covalent Inhibition of CLIC1: A Novel Strategy for Anti-Cancer Drug Discovery

Abstract

Human Chloride Intracellular Channel 1 (CLIC1) is frequently overexpressed in various tumors, where it plays a critical role in cancer cell survival by recycling vitamin C and protecting against oxidative stress. This crucial function makes targeting CLIC1's enzymatic activity a highly promising strategy for developing novel anti-cancer therapies. Despite its significant therapeutic potential, CLIC1 presents a considerable challenge in drug discovery due to its characteristically shallow, solvent-exposed active site. To overcome this hurdle, we implemented a Structure-Based Drug Design (SBDD) approach, specifically focusing on the development of covalent inhibitors. Through a rigorous process involving structure-based covalent docking and atomistic molecular dynamics simulations, we successfully identified and shortlisted several candidate covalent molecules from the NCI library that specifically target the CLIC1 active site. Subsequent in vitro enzyme inhibition assays validated the effectiveness of our approach, successfully screening and identifying three potent inhibitors. To further advance our understanding and facilitate future drug optimization, we have also successfully solved the crystal structure of the CLIC1-covalent inhibitor complex at 1.9 Å resolution, providing invaluable insights into their binding mechanisms and paving the way for further anti-cancer drug discovery.