Structural‐Based Drug Discovery Targeting PCNA: A Novel Cancer Therapeutic

Proliferating Cell Nuclear Antigen (PCNA), which is a member of the sliding clamp family, critically functions as a hub for proteins that are involved in DNA metabolism events, by bringing them into close proximity with DNA. A unique isoform of PCNA has been defined as playing a critical pathological role in multiple tumors, including breast cancer and neuroblastoma. Notably, this cancer associated isoform of PCNA (caPCNA) is highly expressed in cancer cells, but not at significant levels in non‐malignant cells. Thus, we hypothesize caPCNA could act as a novel target for the development of cancer‐selective drugs. By using computer‐aided drug design (CADD) driven approaches, our collaborators at the City of Hope Medical Center have recently identified first‐in‐class small molecules capable of targeting caPCNA and killing caPCNA‐driven cancer cells. Our aim is to characterize these novel compounds by protein crystallography, to aid their development into more drug‐like molecules. Thus far, we have discovered a novel apo‐ PCNA crystallization condition diffracting to 2.1 Å that can be potentially used in our analyses. We have also begun fragment‐based drug discovery (FBDD) studies, to identify novel chemical groups that could be utilized in our drug‐discovery efforts. Through thermal shift screening assays, we have revealed over 70 potential fragment binders that are undergoing structural characterizations. Thus, through combined CADD, FBDD, biochemical and cell‐based assays, our analyses of initial CADD‐based compounds and fragment hits can be used to develop compounds suitable for preclinical studies, and ideally, open a novel therapeutic avenue for the selective targeting of cancers. Support or Funding Information DOD CDRMP BCRP Level 2 award‐ “Breast Cancer Selective Therapeutic Development: Lead Optimization of a Small Molecule Inhibitor of The Breast Cancer Selective Hub Protein caPCNA”