Project No. 2351
Dr Jose L. Ortega-Roldan – University of Kent
Prof John Spencer- University of Sussex
Dr Vahitha Abdul-Salam – Queen Mary University of London
CLIC1 overexpression is associated with high rate of proliferation, migration, neoplastic tissue invasion and resistance of tumours to treatment.
CLIC1 relocalisation from the cytosol to the membrane triggers the pathological activities of CLIC1 where it forms an active ion channel. No specific inhibitor exists for this protein due to the lack of mechanistic information on CLIC1 activation and membrane insertion.
Our studies revealed that Zn2+ triggers CLIC1 membrane insertion and activation into chloride channels and revealed unique targetable hotspots. We also achieved the inhibition of CLIC1 membrane insertion effects using small-molecule compounds selected from a preliminary structure-based in silico screening.
We aim to identify novel highly selective inhibitors of CLIC1 membrane relocalisation to halt its pathological activity supporting tumour development employing a multidisciplinary approach combining structural biology, AI-computational modelling, and cell-based assays Specifically, we will employ a multidisciplinary approach combining structural biology tools (NMR, X-Ray crystallography and Cryo-EM), computational modelling, and cell-based assays. Building on our robust preliminary data, we will;(Aim 1) elucidate the mechanisms of activation and membrane insertion of CLIC1 with molecular detail, (Aim2) identify hotspots altering its relocalisation to the membrane. (Aim 3) use this mechanistic information to target the soluble form of CLIC1 with a data-driven in-silico screening approach to identify novel specific inhibitors with desirable effects on CLIC1 involvement in cancer initiation and progression. Our findings will provide critical and timely structural, mechanistic and molecular information as well as new therapeutic strategies to treat CLIC1-related cancers. More so, knowledge gained from this study can be used to better inform structure-guided design and discovery of next-generation anti-cancer ‘breakthrough’ molecules as optimal treatment solutions.