Destroying cancer-causing proteins

Targeted protein degradation (TPD) is an exciting and emerging modality that is transforming both research and therapeutics. TPD harnesses the cellular protein degradation machinery to target the destruction of specific proteins in cells. The Sapkota lab has pioneered and applied the Affinity-directed PROtein Missile (AdPROM) system to target the degradation of some cancer-causing proteins (PMIDs: 28490657, 32668202) and proteins that are misfolded in neurodegenerative diseases (https://doi.org/10.1101/2025.04.15.648905; https://doi.org/10.1101/2025.05.27.656291).  

Recent work from the Sapkota lab has identified the FAM83 family of poorly characterised proteins as master regulators of CK1 family of protein kinases (PMIDs: 29789297, 31338967). Through an interaction with CK1-alpha, FAM83D ensures proper mitotic spindle alignment and timely progression through cell division and depletion of FAM83D causes mitotic errors and inhibition of cell proliferation (PMID: 31338967). FAM83F and FAM83G activate Wnt signalling through association with CK1-alpha and the attenuation of CK1-alpha interaction and Wnt signalling underlies the pathogenesis of palmoplantar keratoderma caused by FAM83G mutations (PMIDs: 29514862; 33361109; 33361334, 31656861, 39043225). Hyperactive Wnt signalling is associated with colorectal and other cancers, which remain difficult to treat. Because of their roles in promoting cell proliferation, FAM83D, FAM83F and FAM83G represent promising therapeutic targets.  

This PhD project will explore precisely how FAM83D, FAM83F, and FAM83G regulate cell division and cancer cell proliferation, with a particular focus on their degradation as a therapeutic strategy. 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 FAM83D, FAM83F and FAM83G, and development and application of small molecule degraders, including PROTACs and molecular glues, against FAM83D-CK1-alpha, FAM83F-CK1-alpha and FAM83G-CK1-alpha complexes. The aim is to establish a mechanistic foundation and therapeutic rationale for selectively degrading these proteins complexes to suppress cancer cell growth.