The Power of Kinetic Inertness in Improving Platinum Anticancer Therapy by Circumventing Resistance and Ameliorating Nephrotoxicity.

Abstract

Even in the modern era of precision medicine and immunotherapy, chemotherapy with platinum (Pt) drugs remain among the most commonly prescribed medication against a variety of cancers. Unfortunately, the broad applicability of these blockbuster Pt drugs is severely limited by intrinsic and/or acquired resistance, and high systemic toxicity. Considering the strong inter-connection between kinetic lability and undesired shortcomings of clinical Pt drugs, we rationally designed kinetically inert organometallic Pt based anticancer agents with a novel mechanism of action. Using a combination of in vitro and in vivo assays we demonstrated that the development of a remarkably efficacious but kinetically inert Pt anticancer agent is feasible. Along with exerting promising antitumor efficacy in Pt-sensitive as well as Pt-resistant tumors in vivo, our best candidate has the ability to mitigate the nephrotoxicity issue associated with cisplatin. In addition to demonstrating, for the first time, the power of kinetic inertness on improving the therapeutic benefits of Pt based anticancer therapy, we described the detailed mechanism of action of our best kinetically inert antitumor agent. This study will certainly pave the way for designing next generation of anticancer drugs for effective treatment of various cancers.