Reactivating Apoptosis in Refractory Pediatric Cancer by Molecular Inhibition of MCL-1
New treatments are urgently needed to combat relapsed and refractory pediatric cancers. A specialized group of proteins, called the BCL-2 family, regulates the natural balance between cellular life and death, ensuring that essential cells are preserved and damaged cells eliminated.
Cancer cells hijack the survival arm of the BCL-2 family pathway to suppress the cell killing proteins and thereby enforce an immortal state. This is accomplished at the molecular level by a specialized surface on survival proteins, called the "anti-apoptotic groove," which neutralizes a helically-shaped motif, called "the BH3 domain," essential to the killing activity of the death proteins. MCL-1 is a pro-survival BCL-2 family member that has emerged as a ubiquitous chemotherapy and radiotherapy resistance factor in pediatric cancer.
We previously discovered that a synthetic version of the MCL-1 BH3 domain was exquisitely selective at binding and blocking MCL-1. We used this unique reagent to discover a prototype small molecule drug named MCL-1 inhibitor molecule 1 (MIM1), which effectively targeted MCL-1 and blocked its cancer-causing activities in genetically-engineered cells.
Here, we propose to conduct the essential steps to transform our basic science breakthrough into a clinical innovation. Specifically, we aim to apply medicinal chemistry methods to optimize the molecular structure of MIM1 so that it is an ideally potent and selective inhibitor of MCL-1, capable of reactivating the death pathway in the diversity of resistant pediatric cancer cells. Our goal is to bridge chemistry, pediatric cancer biology, and translational medicine to create a next-generation therapeutic modality for pediatric cancer.