Targeted protein degradation (TPD) is an emerging modality for both research and therapeutics. TPD harnesses the cellular protein degradation pathways to target the destruction of target proteins. The Sapkota lab has previously pioneered and applied the Affinity-directed PROtein Missile (AdPROM) system to target the degradation of some cancer-causing proteins (PMIDs: 28490657, 32668202). Hyperactive Wnt signalling is associated with colorectal and other cancers, which remain difficult to treat. The Sapkota lab has discovered that the poorly characterised proteins FAM83F and FAM83G activate Wnt signalling through association with the ser/thr kinase CK1-alpha (PMIDs: 29514862; 33361109; 33361334, 31656861, 39043225). The FAM83 proteins direct CK1 family of kinases to specific subcellular compartments and potentially substrates (PMIDs: 29789297, 31338967). This PhD project aims to understand the molecular mechanisms by which FAM83F and FAM83G activate Wnt signalling and explore if targeted degradation of FAM83F and/or FAM83G inhibits Wnt-dependent proliferation of colorectal and other cancers. The project will employ a wide range of multi-disciplinary cutting-edge technologies, such as CRISPR/Cas9 genome editing, mass-spectrometry, DEL screens to identify ligands for FAM83F/FAM83G, and development and application of small molecule degraders, including PROTACs and molecular glues, of FAM83F-CK1-alpha and FAM83G-CK1-alpha complexes.