Post-translational modifications (PTMs) vastly expand the diversity of human proteome, dynamically reshaping protein activity, interactions, and localization in response to environmental, pharmacologi...

A chemoproteomic strategy reveals how posttranslational modifications reshape protein ligandability across the human proteome, uncovering more than 400 state-dependent interactions, including phosphor...

A chemoproteomic strategy reveals how posttranslational modifications reshape protein ligandability across the human proteome, uncovering more than 400 state-dependent interactions, including phosphor...

Development of targeted covalent inhibitors and covalent ligand-first approaches have emerged as a powerful strategy in drug design, with cysteines be…

Autophagosome tethering compounds (ATTECs) are small molecule degraders hijacking the autophagy system. Here, the authors show that current ATTEC ligands did not bind to their designated targets but e...

The steadily growing number of experimental G-protein-coupled receptor (GPCR) structures has revealed diverse locations of allosteric modulation, and yet few drugs target them. This gap highlights the...

Kazi et al. report the crystal structure of the mitochondrial deubiquitinase USP, a clinical stage Parkinson’s disease drug target, in complex with a specific inhibitor. The authors delineate a framew...

Nature Chemical Biology - A chemoproteomic strategy reveals how posttranslational modifications reshape protein ligandability across the human proteome, uncovering more than 400 state-dependent...

Activity-based protein profiling (ABPP) of stereoisomerically defined sets of electrophilic compounds (‘stereoprobes’) offers a versatile way to discover covalent ligands for proteins in native biolog...

Autophagosome tethering compounds (ATTECs) are small molecule degraders hijacking the autophagy system. Here, the authors show that current ATTEC ligands did not bind to their designated targets but e...

Activity-based protein profiling has identified hundreds of proteins from diverse classes that react at specific cysteine residues with stereochemically defined electrophilic compounds (stereoprobes) ...

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed DrugMap , an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NFκB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity. ### Competing Interest Statement L.B-P. is a founder, consultant and holds privately held equity in Scorpion Therapeutics. Multiple co-authors are employees of Scorpion Therapeutics and some hold equity.

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Abstract. Covalent probes and therapeutics must balance electrophilicity and stability for function in biological systems, yet gains in stability can sacri

The mitochondrial deubiquitinase USP30 negatively regulates Pink1/Parkin-driven mitophagy. Whether e

NF-κB inducing kinase (NIK) is the central regulatory component of noncanonical NF-κB signalling and has been implicated in a variety of cancers and immune disorders. While NIK has been pursued as a t...