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
- Chen Y, et al. Direct mapping of ligandable tyrosines and lysines in cells with chiral sulfonyl fluoride probes. Nat Chem. 2023. PDF
- Yang T, et al. Reversible lysine-targeted probes reveal residence time-based kinase selectivity. Nat Chem Biol. 2022. PDF
- Wan X, et al. Discovery of lysine-targeted eIF4E inhibitors through covalent docking. J Am Chem Soc. 2020. PDF
- Cuesta A, et al. Ligand conformational bias drives enantioselective modification of a surface-exposed lysine on Hsp90. J Am Chem Soc. 2020. PDF
- Cuesta A, Taunton J. Lysine-targeted inhibitors and chemoproteomic probes. Annu Rev Biochem. 2019. PDF
- Zhao Q, et al. Broad-spectrum kinase profiling in live cells with lysine-targeted sulfonyl fluoride probes. J Am Chem Soc. 2017. PDF
- Bradshaw JM, et al. Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat Chem Biol. 2015. PDF
- Serafimova IM, et al. Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles. Nat Chem Biol. 2012. PDF
- Cohen MC, et al. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science. 2005. PDF
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
- Oltion K, et al. An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes. Cell. 2023. PDF
- Rehan S, et al. Signal peptide mimicry primes Sec61 for client-selective inhibition. Nat Chem Biol. 2023. PDF
- Holm M, et al., mRNA decoding in human is kinetically and structurally distinct from bacteria. Nature. 2023. PDF
- Wang HY, et al. Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumor eEF1A antagonist SR-A3. Nat Chem. 2022. PDF
- Juette MF, et al. Didemnin B and ternatin-4 differentially inhibit conformational changes in eEF1A required for aminoacyl-tRNA accommodation into mammalian ribosomes. eLife. 2022. PDF
- Carelli JD, et al. Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex. eLife. 2015. PDF
- Garrison JL, et al. A substrate-specific inhibitor of protein translocation into the endoplasmic reticulum. Nature. 2005. PDF