Synthesis of Veliparib Prodrugs and Determination of Drug-Release-Dependent PARP-1 Inhibition

Abstract

Poly(ADP-ribose) polymerase (PARP) plays a key role in repairing DNA damage, and several PARP inhibitors have been approved as treatments in BRCA1/2 mutated breast and ovarian cancers. Mounting evidence also supports their application as neuroprotective agents since PARP overactivation compromises the mitochondrial homeostasis by consumption of NAD+ reserves, leading to an increase in reactive oxygen and nitrogen species and a spike in intracellular Ca2+ levels. Herein, we present the synthesis and preliminary evaluation of new mitochondria-targeting PARP inhibitor prodrugs of (±)-veliparib, with the goal to advance potential neuroprotective properties without impairing the repair of damaged DNA in the nucleus.

Mechanisms of PARP-Inhibitor-Resistance in BRCA-Mutated Breast Cancer and New Therapeutic Approaches

“…Currently, there are four FDA-approved PARP inhibitors: (olaparib AZD2281 IC50 = 5 nM [40]; rucaparib AG15699 IC50 = 7.1 nM [41]; niraparib MK4827 IC50 = 3.8 nM [42]; and talazoparib BMN 673 IC50 = 0.57 nM [43]). They can be used for the treatment of patients [44][45][46]; and, there are an additional two inhibitors: (veliparib ABT888 IC50 = 3.3 nM [47] and pamiparib BGB290 IC50 = 1.3 nM [48]). They are undergoing clinical trials and evaluation [49].…”

“…The most successful aspect of PARP-inhibition is limiting tumor progression due to a lack of proper homologous recombination for DNA repair, causing tumor cell death while normal cells remain unaffected [46,47]. A second treatment strategy involving the use of PARP inhibitors is the use of combination regimens, including cytotoxic chemotherapy, anti-angiogenic drugs, radiotherapy, immune therapy, and DNA damage-protein-inhibition [43].…”