Chimeric PARP/NAMPT inhibitors have been designed to be phosphoribosylated by NAMPT (nicotinamide phosphoribosyltransferase). This modification enriches the cytotoxic adducts held within cancer cells that overexpress NAMPT and significantly increases the safety and efficacy of PARP inhibition, minimizes resistance, and promotes further cancer cell death. Intended to be used in combination with PARP inhibitors. Primary indication is Triple Negative Breast Cancer but can be utilized in all cancers with NAMPT upregulation. Background: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer. TNBC has 50% mortality with a lack of approved targeted therapies. Although TNBC accounts for only 10-20% of breast cancers overall, in African American women up to 40% of all diagnoses are TNBC. The heterogeneity of TNBC represents a major obstacle to precision medicine thus novel precision therapeutic approaches to TNBC are keenly needed. Nicotinamide phosphoribosyltransferase (NAMPT) is upregulated in many cancers, including the majority of TNBC cells and tumors and in several cancers NAMPT upregulation is a mechanism of acquired resistance. So far NAMPT inhibitors have not proceeded past Phase 1 clinical trials, owing to unconvincing efficacy versus safety. Additionally, up to 10% of TNBC patients carry germline BRCA1/2 mutations that provide a clinical biomarker for treatment with DNA-targeting cytotoxic agents, such as organo-platinum agents and poly(ADP-ribose) polymerase (PARP) inhibitors. Here, the inventors have synthesized and optimized chimeric PARP/NAMPT inhibitors, which provide an advantage over current TNBC therapeutics. This combination of inhibitors has been demonstrated in cell cultures and potentially addresses the current limitations of targeted therapies in TNBC, in addition to sensitizing tumors to immune checkpoint inhibitors. Applications:
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