Proliferating cell nuclear antigen (PCNA) is a homotrimer protein that encircles the DNA during DNA replication and acts as a scaffold to recruit proteins involved in DNA replication, DNA repair, chromatin remodeling, and epigenetics which are key molecular processes in ontogenesis. The cancer-associated isoform of PCNA (caPCNA) is a unique isoform of PCNA that is highly expressed in cancer cells and plays a critical role in the pathology of breast cancer. Recently, the Hickey and Malkas laboratories have developed two lead compounds (AOH1996 and AOH1160) that selectively inhibit caPCNA and have been successfully validated in vitro using cellular assays and in vivo, using animal models. In the lead optimization stage, we have designed (via Schrödinger suite) and synthesized specific analogues in which the bridging oxygen between two phenyl rings was replaced by other functional groups such as a carbonyl (C=O), imido (NH), sulfur (S), sulfonyl (SO2), mono- and di-halo methylene (CXY). Similarly, the glycine linker in the parent analogues has been replaced by other common amino acids (natural and unnatural) for the purpose of a comprehensive SAR study to improve their potency and selectivity toward cancer cells. Moreover, to enhance their bioavailability and targeted delivery to cancer cells, we are investigating the 6-maleimidocaproyl hydrazone derivative of AOH compounds (EMCH-AOH). The introduction of EMCH is a known prodrug approach that has demonstrated superior antitumor efficacy in murine tumor models. EMCH is an acid-sensitive linker that will be released from the drug in the acidic environment of tumor cells. This modification requires the introduction of a carbonyl function to AOH that EMCH can bind to it. Thus, we have performed in silico studies using the Schrödinger suite to introduce a carbonyl function to an appropriate place in the AOH compounds to maintain the key interactions with the PIP box domain of PCNA. The synthesis, characterization, modeling data and biological activities of these novel AOH analogues will be described.

Novel cancer-associated PCNA small-molecule inhibitors: Design and synthesis of AOH analogues for SAR study

ACS Spring 2022

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