Hijacking the natural mechanism of the Ubiquitin Proteasome System (UPS) is emerging as a powerful medium in drug discovery through which Dr. Kadimisetty uses “TUBEs” as ubiquitin-binding entities to monitor PROTAC-mediated poly-ubiquitination of target proteins. The technology described wherein is a direct way to evaluate and discover PROTAC and molecular glue targets for use in drug discovery.
This paper is published in the Biochemical and Biophysical Research Communications (BBRC), an international scientific journal devoted to the rapid dissemination of timely and significant experimental results in biological research.
Dr. Kadimisetty’s paper demonstrates how ubiquitination kinetics can establish the rank order potencies of PROTAC with variable ligands and linkers, allowing additional insight into the functionality of the UPS.
Introduction
PROTACs have emerged as a new class of drugs that can target the “undruggable” proteome by hijacking the ubiquitin proteasome system. Despite PROTACs’ success, most current PROTACs interface with a limited number of E3 ligases, hindering their expansion to many challenging therapeutic uses. Currently, PROTAC drug discovery relies heavily on traditional Western blotting and reporter gene assays which are insensitive and prone to artifacts, respectively. New reliable methods to monitor true PROTAC function (i.e., ubiquitination and subsequent degradation of targets at physiological expression levels) without external tags are essential to accelerate the PROTAC discovery process and to address many unmet therapeutic areas. In this study, we developed a new high-throughput screening technology using
“TUBEs” as ubiquitin-binding entities to monitor PROTAC-mediated poly-ubiquitination of native target proteins with exceptional sensitivity.