Ubiquitin-mediated signaling plays a central role in the control of protein degradation. Ubiquitin ligases synthesize polyubiquitin chains on target proteins, which are then degraded by the proteasome. The era of PROTAC drugs (proteolysis-targeting chimeras) was launched by the emergence of new concepts in medicinal chemistry, wherein small molecules are designed to contain groups that bind to a ubiquitin ligase at one end and to the target protein at the other end, leading to proteasome-mediated degradation of the target protein. PROTACs recruit cellular protein degradation machinery for polyubiquitination and subsequent proteasomal degradation. While this concept is quite promising, there are major hurdles in developing new PROTAC drugs. Medicinal chemists rapidly synthesize a variety of PROTAC molecules, which must then be tested in laborious cell-based assays to monitor degradation of target proteins by immunoblotting. The rate of development of novel PROTAC designs has surpassed the existing capacity to validate their ability to recruit respective E3 ligase(s) and candidate substrates and to effect polyubiquitination and degradation of the target. Currently, no efficient methods are available to validate the ubiquitination ability of newly designed PROTACs. Here we propose to develop a novel high-throughput method to screen polyubiquitination and degradation properties of PROTACs. This technology will help medicinal chemists to design PROTAC drugs in a rational way and accelerate the development of PROTACs in new therapeutic areas.

Public Health Relevance

PROTACs (PROteolysis TArgeting Chimeras) are novel experimental drugs, in which a Ub E3 ligase binding molecule is linked chemically to a target protein binding molecule; when the ligase and target protein are brought together, the target is degraded for therapeutic effect. The 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 use. Progenra proposes a new cell-based assay that increases the throughput and eliminates artifacts; this assay will enable development of new PROTACs that can treat heretofore unaddressed diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43GM134737-01
Application #
9843849
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Marino, Pamela
Project Start
2019-07-01
Project End
2020-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Lifesensors, Inc.
Department
Type
DUNS #
060013641
City
Malvern
State
PA
Country
United States
Zip Code
19355