Abstract P098: A chemoproteomic platform for identifying small-molecule modulators of protein-protein interactions, discovering new cancer targets, and revealing previously unknown targets for well-known drugs

Abstract

BridGene Biosciences has developed a novel chemoproteomic platform IMTACTM (Isobaric Mass-Tagged Affinity Characterization) for discovering small-molecule inhibitors of protein-protein interactions, disclosing new cancer targets, and identifying previously unknown targets for known drugs. The key components of the IMTACTM platform include a unique library of drug-like covalent small molecules containing an alkyne tag, live-cell screening, and quantitative mass spec analysis. The IMTACTM analysis begins with treating live cells with probes from the covalent library, proceeds with enrichment of the probe-modified proteins, and then employs Mass Spec to identify the probe-modified proteins and determine the relative binding affinity. This powerful chemoproteomic platform enables systematic mapping of the direct interactions of small-molecules across the proteome. A prominent application of BridGene’s IMTACTM platform is to identify hits for “hard to drug” targets from live-cell screening. IMTAC TM screening is well suited for identifying drug-like ligands for such hard-to-drug targets, including those with shallow binding pockets or temporary pockets formed under certain cellular settings. Lead optimization can be immediately initiated after confirmation of the ligand’s binding to relevant targets. Using the IMTACTM platform, BridGene has discovered small-molecule ligands for a number of “hard-to-drug” targets as well as oncogenic mutants, including GTPases (e.g. RhoA), transcription factors (e.g. TEAD), splicing factors (e.g. SRSF1), epigenetic modulators (e.g. WDR5), E3 ligases, etc. The potency of the hits ranges from low nanomolar to micromolar. Because of the IMTACTM platform’s proteome-wide profiling capability, BridGene has also, for the first time, revealed new targets for some well-known drugs. Combining IMTAC TM screening with phenotypic screening, BridGene is also discovering new/unknown targets that drive certain disease phenotypic changes. IMTACTM is a novel platform to discover small molecule drugs for hard-to-drug targets. It allows the mapping of targets for small molecules on a proteome-wide scale, which can provide comprehensive selectivity information to facilitate lead optimization and lower off-target toxicity. IMTACTM has the potential to redefine precision medicine, discover new drugs and new targets, and identify new indications of known drugs. Citation Format: Cindy Huang, Vivian Zhang, Ning Deng, Irene Yuan, Linda Pullan, C. Glenn Begley, Ping Cao. A chemoproteomic platform for identifying small-molecule modulators of protein-protein interactions, discovering new cancer targets, and revealing previously unknown targets for well-known drugs [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P098.