Abstract P156: Identification of previously unknown targets for approved small-molecule drugs using chemoproteomic platform IMTACTM

Abstract

Abstract Small-molecule drugs exert their therapeutic effects through binding and modulating functions of their target proteins. While most approved drugs have defined target(s), a comprehensive target map is generally lacking for clinical and experimental drugs. This limits both understandings of a drug’s actions and hampers further optimization. Leveraging its proprietary chemoproteomic platform IMTACTM, BridGene Biosciences has developed an approach to generate more comprehensive target maps for approved small-molecule drugs. This approach can also be applied to drug candidates. The approach was successfully applied to a covalent drug ibrutinib and a non-covalent drug sunitinib, revealing previously unknown targets of these drugs. The drug, sunitinib or ibrutinib, was first chemically modified to generate probe compounds, which were then treated on live cells. Quantitative mass spec analysis of the resulting proteomes was performed to identify the binding targets and quantify their apparent binding affinity to the drug. The identified probe-binding proteins were then ranked based on their apparent binding affinity to determine the proteome-wide selectivity to the drug. BridGene’s IMTACTM profiling verified BTK to be the top target and two other kinases (BLK and TEC) to be prominent targets of ibrutinib in Ramos cells. Analogous IMTACTM profiling confirmed sunitinib’s binding to over a dozen of protein kinases with high to moderate affinity in Ramos cells. The kinase targets of sunitinib in Ramos cells include BLK, LYN, PTK2B, etc. Importantly, non-kinase targets included metabolic enzymes were also identified for ibrutinib and sunitinib in the IMTACTM profiling. The binding of the drugs to select new targets was verified using biochemical or binding assays. Our study demonstrates that IMTACTM profiling is a powerful approach for generating comprehensive target maps for clinical and experimental drugs, both covalent and non-covalent ones. Having target scope information will be invaluable at various stages of drug discovery and development, such as the repurposing of existing drugs, the optimization of drug candidates, as well as target identification and deconvolution for phenotypic screening hits. Citation Format: Vivian Zhang, Cindy Huang, Chao Zhang, Ping Cao. Identification of previously unknown targets for approved small-molecule drugs using chemoproteomic platform IMTACTM [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 P156.