Rational design of bifunctional protein degrader drugs

Ubiquitin mediated signaling plays a central role in the control of protein degradationUbiquitin ligases synthesize polyubiquitin chains on target proteinswhich are then degraded by the proteasomeThe era of PROTAC drugsproteolysis targeting chimeraswas launched by the emergence of new concepts in medicinal chemistrywherein small molecules are designed to contain groups that bind to a ubiquitin ligase at one end and to the target protein at the other endleading to proteasome mediated degradation of the target proteinPROTACs recruit cellular protein degradation machinery for polyubiquitination and subsequent proteasomal degradationWhile this concept is quite promisingthere are major hurdles in developing new PROTAC drugsMedicinal chemists rapidly synthesize a variety of PROTAC moleculeswhich must then be tested in laborious cell based assays to monitor degradation of target proteins by immunoblottingThe rate of development of novel PROTAC designs has surpassed the existing capacity to validate their ability to recruit respective Eligase sand candidate substrates and to effect polyubiquitination and degradation of the targetCurrentlyno efficient methods are available to validate the ubiquitination ability of newly designed PROTACsHere we propose to develop a novel high throughput method to screen polyubiquitination and degradation properties of PROTACsThis technology will help medicinal chemists to design PROTAC drugs in a rational way and accelerate the development of PROTACs in new therapeutic areas PROTACsPROteolysis TArgeting Chimerasare novel experimental drugsin which a Ub Eligase binding molecule is linked chemically to a target protein binding moleculewhen the ligase and target protein are brought togetherthe target is degraded for therapeutic effectThe ability to design new PROTACs that work on an expanded range of therapeutic targets is hindered by inadequate cell assays currently available to guide chemical improvement of the molecule for clinical useProgenra proposes a new cell based assay that increases the throughput and eliminates artifactsthis assay will enable development of new PROTACs that can treat heretofore unaddressed diseases