A bottleneck in drug discovery is the lack of high-quality small-molecule probes to validate the disease relevance of genes, particularly those with promising disease linkage but are considered ?undruggable?, such as transcription factors and scaffolding proteins. Recently, covalent drugs have become a promising option to address a number of challenges such as low efficiency of lead discovery, resistance to targeted therapies, and poor druggability of many targets. We hypothesize that the druggable targets can be dramatically expanded by leveraging covalent chemistry in drug development. The TarGead Sciences team proposes to combine bio-orthogonal reactions with MS- based proteomics technology to create a novel platform that allows for the detection and quantification of the interactions between an electrophilic compound and thousands of proteins across the proteome. Specifically, we will synthesize a library of electrophilic probes based on privileged scaffolds as baits to fish out novel targets in various cell types (Aim 1). A new chemical proteomic approach will be established to map and quantify the proteome-wide interactions of electrophilic probes in different cell lines (Aim 2).
In Aim 3, we will optimize electrophilic leads for potent and selective functional modulation of select targets such as vacuolar ATPase. Our work will yield high-quality covalent leads for novel targets including the undruggable ones, paving the way for subsequent preclinical studies.

Public Health Relevance

TarGead Sciences aims to develop a novel chemical proteomic platform to expand druggable space. The proposed work will open new frontiers in drug discovery, and greatly accelerate the discovery of new therapeutics in the treatment of serious or life- threatening conditions.

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 #
1R43GM130180-01
Application #
9619996
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Krepkiy, Dmitriy
Project Start
2018-09-15
Project End
2019-09-14
Budget Start
2018-09-15
Budget End
2019-09-14
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Targead Sciences, Inc.
Department
Type
DUNS #
080774728
City
Burlingame
State
CA
Country
United States
Zip Code
94010