Systematic Targeting of Protein Complexes with Molecular COUPLrs
Author:
Yang Diane, Harry Stefan Andrew, Chong Harrison Byron, Zhang Edwin, Nordenfelt Natalie Shannon, Chen Nicholas, Lee Christine, Kaluziak Stefan, Codd Elizabeth, Trivedi Samay, Gohar Magdy, McKnight Giovan, Mitchell Dawn R., Ge Maolin, Gao Chengzhuo, Holmes Zavontae, Yang Wenxin, Smith Abigail Elizabeth, Carlin Alexander Daniel, Lazarov Matthew J., Khandelwal Neha, Hara Mariko, Zhang Siwen, Leong Herman Xin Yang, Martinez Luna Hector, Chearavanont Zander, Emonds Kim, Popoola George, Barakat Idris, Onozato Maristela, Mahamdeh Mohammed, Fujino Toshio, Seo Hyuk-Soo, Dhe-Paganon Sirano, Sun Zhen-Yu Jim, Heffron Gregory J, Hata Aaron, Soberman Roy Jason, Liau Brian B.ORCID, Iafrate A. John, Bar-Peled Liron
Abstract
AbstractMolecular glues that engage protein complexes have transformed the study of cell biology and have had a direct impact on clinical oncology. However, the identification of new glue classes and their corresponding protein complexes has remained largely serendipitous. To overcome this challenge, we report the development of molecular COUPLrs, elaborated small molecules flanked by two cysteine-reactive warheads, as well as CONNECT, an integrated chemical proteomic platform for target deconvolution. By profiling a library of molecular COUPLrs across 13 cancer cell lines, we uncovered hundreds of proteins that can be coupled together, including in some cases in mutant selective fashions. We develop an advanced COUPLr for the oncogene EML4-ALK, which engages the fusion outside of its kinase domain, restricts protein dynamics, and disrupts EML4-ALK signaling. Collectively, molecular COUPLrs substantially expand the scope of proteins that can be chemically connected, providing an unbiased approach to identify small molecules that target protein complexes.
Publisher
Cold Spring Harbor Laboratory
|
|