AOH1996

AOH1996 is an orally available and metabolically stable small molecule PCNA inhibitor, which selectively kills cancer cells, with a median concentration of about 300 nM for 50% growth inhibition. AOH1996 was not significantly toxic to non-malignant cells, even up to 10 µM. AOH1996 enhances the interaction between PCNA and the largest subunit of RNA polymerase II (RNAPII), RPB1, and dissociates PCNA from actively transcribed chromatin regions, while inducing DNA double-stranded breaks in a transcription-dependent manner, leading to the overall degradation of RPB1 and the collapse of replication forks in actively transcribed regions. AOH1996 was created to target a post-translationally modified isoform of PCNA, termed caPCNA, which is preferentially found in cancer cells. PCNA is crucial in the body for DNA repair, but targeting it is difficult because of its role in healthy cells. By selectively targeting caPCNA, it may be possible to kill cancer cells without affecting healthy tissues. In vitro testing demonstrated that AOH1996 inhibited the growth and induced cell cycle arrest (G2/M or S phase arrest) and apoptotic cell death in a wide variety of cancer cell lines, but had no effect on several normal, nonmalignant cell types.