Development of Platinated Poly(ADP-Ribosyl)ation Modulators as Novel Antineoplastic Agents

Description

The proposed research focuses on the development of novel platinum-conjugated poly(ADP-ribosyl)ation modulators as anticancer complexes. Poly(ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in clinical trials for cancer treatment in combination with traditional platinum-based anticancer drugs including cisplatin. We aim to synthesize conjugates that contain active moieties of cisplatin and of PARP inhibitors as novel antineoplastic agents that may be more potent than the original PARP inhibitors and overcome cisplatin resistance. Pt(II) or Pt(IV) units will be conjugated with PARP inhibitors or inhibitors of poly(ADP-ribose) glycohydrolase (PARG). Biochemical assays will be performed to test if the conjugates hit their targets. Cell-based assays will be carried out to confirm that the conjugates act on the desired targets and kill cancer cells. In summary, the proposed research will not only generate novel dual-targeting antineoplastic agents, but also open a new and innovative chemotherapeutic window using a single agent targeting both DNA and poly(ADP-ribose) metabolism.