A Novel Chemical Proteomics Platform to Expand Druggable Space

Abstract A bottleneck in drug discovery is the lack of high quality small molecule probes to validate the disease relevance of genesparticularly those with promising disease linkage but are consideredundruggablesuch as transcription factors and scaffolding proteinsRecentlycovalent drugs have become a promising option to address a number of challenges such as low efficiency of lead discoveryresistance to targeted therapiesand poor druggability of many targetsWe hypothesize that the druggable targets can be dramatically expanded by leveraging covalent chemistry in drug developmentThe TarGead Sciences team proposes to combine bio orthogonal reactions with MSbased 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 proteomeSpecificallywe will synthesize a library of electrophilic probes based on privileged scaffolds as baits to fish out novel targets in various cell typesAimA new chemical proteomic approach will be established to map and quantify the proteome wide interactions of electrophilic probes in different cell linesAimIn Aimwe will optimize electrophilic leads for potent and selective functional modulation of select targets such as vacuolar ATPaseOur work will yield high quality covalent leads for novel targets including the undruggable onespaving the way for subsequent preclinical studies