As a member of the sliding clamp family, the Proliferating Cell Nuclear Antigen (PCNA) critically functions as a hub for proteins involved in DNA metabolism events in close proximity to DNA. Recently, a unique isoform of PCNA has been defined as playing a critical pathological role in various cancers, which includes breast cancer. Notably, this cancer associated isoform of PCNA (caPCNA) is highly expressed in cancer cells, but not at significant levels in non-malignant cells. Recently, our collaborators at the City of Hope Medical Center have identified and developed a set of “first-in-class” small molecules that inhibit caPCNA hub activity in vitro, in cellulo and in vivo, which drive cancer cell death while not affecting non-malignant cells. However, these City of Hope computer aided-drug design (CADD)-based molecules are highly hydrophobic in nature, potentially limiting their bioavailability. We hypothesize that structure-based drug design (SBDD), with a focus on fragment-based drug discovery (FBDD), will allow for the identification of functional groups that can be used to enhance the City of Hope leads and for the development of novel drug-like inhibitors in different areas of chemical space. We have screened over 3,550 drug-like fragments and artificial intelligence (AI)-CADD generated binders revealing 246 promising hits that increase protein thermal stability 2°C or greater, indicating potential binding interaction. Utilizing a micro-seeding technique, we have developed a stable crystallization condition of caPCNA diffracting to 2.4 Å, which will be used to characterize ligand:caPCNA interactions via soaking and co-crystallization studies. Characterization of these binding interactions complemented by activity assays, will enable subsequent SBDD studies to develop hit molecules with improved solubility and stability for lead optimization.