We developed DrugMap, a cysteine reactivity atlas across 416 cancer cell lines, uncovering context-specific ligandability driven by redox, conformation, and genetics. This enabled covalent targeting of NFκB1 and SOX10. We further introduced molecular COUPLrs—dual warhead ligands—and CONNECT proteomics, revealing hundreds of inducible protein couplings. A COUPLr targeting EML4-ALK disrupted signaling. Together, these tools map and reprogram protein interactions to access undruggable cancer targets.

Small molecules inducing protein degradation via ligase-mediated ubiquitylation are promising in pharmacology. To comprehensively explore the target space of CRBN, we developed a sensitive and high-throughput lysate-based IP-MS pipeline for unbiased identification of molecular glue targets of IMiD-CRBN. Our study offers a broad catalog of CRBN-recruited targets (>290 targets) and introduces a scalable workflow for discovering new drug-induced protein interactions in cell lysates.

Covalent modulation of therapeutic targets is an increasingly important modality for drug discovery, particularly after recent success with historically challenging targets like KRAS G12C. In this talk, I’ll present the work we have done to discover covalent inhibitors for two different targets, and also describe the chemical biology approaches to understand the selectivity and mechanisms of action of these inhibitors.

We developed COOKIE-Pro, a new method to quantify the binding kinetics of covalent inhibitors across the entire proteome. Using mass spectrometry, it determines kinetic values (kinact?/KI?) for both on- and off-target proteins. We validated COOKIE-Pro with BTK inhibitors, reproducing known parameters and identifying novel off-targets. This powerful tool helps optimize the potency and selectivity of covalent drugs, aiding preclinical development by providing a comprehensive view of inhibitor binding.

I will describe sulfonyl-triazoles as an enabling electrophile for developing covalent binders to tyrosine and lysine residues on proteins through sulfur-triazole exchange (SuTEx) chemistry. SuTEx chemistry is highly tunable with respect to protein reactivity and specificity, which can facilitate optimization of potent and selective binders to orthosteric and allosteric sites on kinases. I will conclude my talk by describing efforts to apply SuTEx ligands for modulating kinase function in cells.