Design and Development of CARP-1-NEMO Binding Inhibitors for Breast Cancer

Abstract

Cancer continues to be a leading global health concern. Despite notable progress in current chemotherapeutics, drug resistance often contributes to treatment failure and poor prognosis. NF-κB signaling pathway has been long considered a prime regulator of normal biological processes and tumor cell survival, proliferation, and growth, which often contributes to resistant phenotypes. One reason for the resistance is the activation of DNA damage-induced canonical NF-κB that is transduced in part by interaction of CARP-1 protein with NF-κB activating kinase subunit gamma or NEMO. High throughput screening (HTS) of the chemical library yielded a selective NF-κB inhibitor (SNI)-1 that showed remarkable inhibition of CARP-1 and NEMO interaction in vitro, and consequent loss of canonical NF-κB activation that resulted in elevated cytotoxicity of chemotherapeutics adriamycin or cisplatin in vitro and in vivo. We aimed to synthesize and evaluate the selective NF-κB inhibitor (SNI)-1 analogs to improve their solubility, stability, and efficacy of cytotoxic chemotherapy. We are utilized Structure-Activity Relationship (SAR) strategies to identify a series of compounds. Several modifications and changes in specific moieties in SNI-1 were predicted to enhance compound drug-like properties such as solubility and biological activity. To date, we identified a few lead compounds that showed better potential to inhibit cell viability of different breast cancer cell lines compared to the parent compound. Our lead compounds GL-213, GL-216, GL-252, GL-269, and GL-340, GL-341, GL-342, and GL-343 have shown an effect on cell viability on their own, and in some instances, greater enhancement of chemotherapeutic efficacies in vitro assays. Thus, targeting of CARP-1 binding with NEMO has the potential to offer novel tools or strategies to combat various breast cancer and their drug-resistant variants. Outcomes of our current SAR studies are expected to identify additional potent drug-like lead compounds that will function in part by abrogating chemotherapy-induced NF-κB signaling activation and help minimize the development of drug-induced resistance and toxicities in breast cancers.