Research

Covalent inhibitors and chemoproteomic probes

Our lab uses chemical biology approaches to study signaling pathways relevant to cancer and autoimmune disease. We work at the earliest stages of covalent drug discovery, developing new chemical tools and methods. For example, we found that cyanoacrylamide-based inhibitors can form reversible covalent bonds with noncatalytic cysteines. These observations led to the discovery of rilzabrutinib, a reversible covalent BTK inhibitor in clinical trials. A current focus is the design and discovery of ligands that covalently modify lysine and tyrosine. We use advanced chemoproteomic technologies to quantify target engagement in cells and animals, as well as X-ray crystallography to optimize probes and elucidate general principles of covalent molecular recognition.

Selected publications


Chemical biology of cyclic peptide natural products

We are fascinated by biologically active natural products, especially macrocyclic peptides with potential anticancer activity. Our studies have revealed mechanistic insights into cellular proteostasis and inspired new therapeutic approaches. Recent work on ternatin cyclic peptides, which trap the eukaryotic elongation factor-1A (eEF1A) on the ribosome, unveiled a quality control pathway comprising two poorly characterized E3 ligases, RNF14 and RNF25, and the ribosome collision sensor, GCN1. Our discovery of the RNF14/RNF25/GCN1 surveillance pathway raises many exciting questions for future research.

Our work on cotransins – cyclic peptides that inhibit the Sec61 translocon in a client-selective manner – has inspired the development of drug candidates with potent anticancer and anti-inflammatory activity. A major unanswered question is how structurally distinct cotransins selectively inhibit the biogenesis of distinct Sec61 clients (secretory and membrane proteins), including many therapeutic targets involved in cell signaling.

Selected publications