Jetze J. Tepe
Michigan State University USA
Title: Natural Product Inspired Scaffolds Design: A closer look at mechanistically distinct proteasome inhibitors
Biography
Biography: Jetze J. Tepe
Abstract
Natural products isolated from plant, animal or fermentation has long been the main source for compounds used in the chemotherapeutic intervention of cancer. However, in the later part of the 20th century, the advances of combinatorial chemistry have taken center stage in the drug discovery process and natural product synthesis took a temporary backseat for these new chemical processes. Combinatorial techniques and compound repurposing have resulted into large libraries in a very cost-efficient manner that can be screened for their biological activities against a desired target. Although cost-effective, these libraries suffer from a lack of diversity with respect to the structural complexity, stereochemistry and chemical space. In addition, the enforcement of restrictions of structural complexity and “drug ability rules”, further narrows the chemical space and thus limits the discovery of novel drug-target interactions. The goal of our program is to discover mechanistically distinct drug-target interactions by generating small libraries with high levels of structural diversity. Our approach is to simulate the structural complexity found in natural products and translates this into structurally diverse abridged scaffolds. Phenotypic screening of these abridged scaffold libraries followed by target identification resulted into two mechanistically distinct classes of proteasome inhibitors. In today’s presentation we will discuss this approach and the ability of these agents to overcome acquired drug resistance and effectively modify the onset of various diseases, such as multiple myeloma and rheumatoid arthritis, in vivo.