UNDERSTANDING THE MECHANISM-OF-ACTION OF PLATINUM(II)-BASED TYPE II ICD INDUCERS THROUGH PURPOSEFUL SCAFFOLD MODIFICATIONS

Abstract

This thesis discusses the immunotherapeutic potential of certain chemotherapeutics by investigating their ability to induce an immunostimulatory form of cell death called Immunogenic Cell Death (ICD). Cancer cells undergoing ICD can function as cancer vaccines to induce the immune system to develop a specific, long-lived, and efficacious anticancer immune response, resulting in immunization of the hosts against future, recurrent cancers. Nevertheless, the structural and mechanistic differences between chemotherapeutic ICD inducers have made identifying a common ICD-inducing pharmacophore or mechanism-of-action difficult.

Hence, we attempt to elucidate the common mechanism-of-action of ICD induction invoked by a platinum(II)-based ICD inducer, Pt-NHC. This is accomplished through the purposeful modification of Pt-NHC’s scaffold to generate analogues of similar structures and mechanisms but with significantly different bioactivities. These analogues are compared to Pt-NHC in their efficiencies in inducing ICD and other biological effects to identify important structural and mechanistic features that are critical for ICD induction.