Roughly 400 protein drivers of carcinogenesis have so far been identified in cells, but only about 10% of these have been effectively targeted, and most of them are protein kinases—which add phosphate groups to proteins—or other enzymes. Drugs that target oncogenic drivers in different ways include a set whose members covalently and irreversibly bind the amino acid cysteine on proteins. These drugs have had some success in the clinic. Researchers co-led by Ludwig Harvard’s Liron Bar-Peled applied proteomics methods to identify new targetable cysteines in key cellular proteins. They reported in Cell in April a quantitative portrait of such “cysteine-ligandability” across more than 400 cancer cell lines, establishing an initial framework for a cysteine ligandability map. Liron and his colleagues found that the variability in responses to cysteine-targeting stems in part from differences in the redox environment of cancer cells and mutations near the targeted cysteines. They applied discoveries made using their dataset, named “DrugMap,” to develop covalent ligands that disrupted the oncogenic activity of transcription factors NF-κB1 and SOX10. DrugMap, they suggest, could help systematically uncover the rules for cysteine ligandability and aid drug development.
DrugMap: A quantitative pan-cancer analysis of cysteine ligandability
Cell, 2024 April 22