Selective Disruption of Replication in Cancerous Cells by Targeting PCNA
The future of cancer therapy will involve the targeting of mechanisms found broadly in many or all different types of cancer, that cancer cells cannot dispense with as they evolve rapidly within a tumor, and which have little to no effect on non-cancerous cells. Targeting telomerase to prevent the lengthening of telomeres can check the first two of those boxes, leaving the question of how best to effectively restrict the treatment to tumor cells. Targeting alternative lengthening of telomeres can check the second and third boxes, but the mechanism only operates in a minority of cancers. The research community is engaged in finding other approaches that might satisfy some of these goals; a few candidates exist. The research noted here is one example of a potentially broadly applicable strategy that disrupts cancer cell replication.
Proliferating cell nuclear antigen (PCNA) is an evolutionarily conserved multifaceted protein found in all eukaryotic cells, and it plays a critical role in DNA synthesis and in DNA repair. PCNA forms a ring structure encircling DNA and it acts as a central "hub" to provide an anchorage for the many proteins involved in the replication and repair pathways. The cellular functions of PCNA can be modulated through post-translational modifications on the surface of the protein, altering partner interactions. Historically, PCNA has been widely used as a tumor progression marker.
DNA replication stress is a hallmark of cancer cells. It is used as a major anti-cancer therapeutic strategy by exploiting this cancer-associated feature, through introduction of further DNA damage resulting in catastrophic damage to the cancer cell. Due to its central role in DNA replication and repair, PCNA is a potential target for this anti-cancer strategy. Moreover, the identification of a distinct isoform of PCNA associated with cancer cells has potentially opened a novel avenue for the development of new chemotherapeutics. Early effects in targeting PCNA have identified several molecules of interest, both small molecule and peptide-based, which have indicated that directly targeting PCNA for cancer therapy may be a viable approach.
We previously described a compound, AOH1160, functioning as a potential inhibitor hit compound of the cancer-associated PCNA isoform (caPCNA), but this compound lacked suitable metabolic properties to proceed further into preclinical/clinical studies. Here, we describe both the identification and detailed molecular characterization of AOH1996, an analog of AOH1160 that exhibits remarkable therapeutic properties: it is orally administrable in a formulation compatible with its clinical use, and in animal studies it almost completely inhibits the growth of xenograft tumors. AOH1996 causes no discernible toxicity at 6 or more times the effective dose in mice and dogs.