Covalent Proximity Inducers DOI Creative Commons
Nir London

Chemical Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 18, 2024

Molecules that are able to induce proximity between two proteins finding ever increasing applications in chemical biology and drug discovery. The ability introduce an electrophile make such inducers covalent can offer improved properties as selectivity, potency, duration of action, reduced molecular size. This concept has been heavily explored the context targeted degradation particular for bivalent molecules, but recently, additional reported other contexts, well monovalent glues. is a comprehensive review inducers, aiming identify common trends current gaps their discovery application.

Language: Английский

Implications of frequent hitter E3 ligases in targeted protein degradation screens DOI
Xiaoyu Zhang, Gabriel M. Simon, Benjamin F. Cravatt

et al.

Nature Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Language: Английский

Citations

0
Proteomic Ligandability Maps of Phosphorus(V) Stereoprobes Identify Covalent TLCD1 Inhibitors DOI
Hayden A. Sharma,

Michael Bielecki,

Meredith A. Holm

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: April 23, 2025

Activity-based protein profiling (ABPP) of stereoisomerically defined sets electrophilic compounds ('stereoprobes') offers a versatile way to discover covalent ligands for proteins in native biological systems. Here we report the synthesis and chemical proteomic characterization stereoprobes bearing P(V)-oxathiaphospholane (OTP) reactive group. ABPP experiments identified numerous human cancer cells that showed stereoselective reactivity with OTP stereoprobes, confirmed several these liganding events recombinant proteins. engaging poorly characterized transmembrane TLCD1 impaired incorporation monounsaturated fatty acids into phosphatidylethanolamine lipids cells, lipidomic phenotype mirrored genetic disruption this protein. Using AlphaFold2, found structurally resembles ceramide synthase acid elongase families coenzyme A-dependent lipid processing enzymes. This structural similarity included conservation catalytic histidine residues, mutation which blocked stereoprobe remodeling activity TLCD1. Taken together, data indicate acts as acyltransferase function inhibitors enzymatic activity. Our findings thus illuminate how analysis can facilitate functional annotation inhibition key metabolic enzyme cells.

Language: Английский

Citations

0
Covalent Proximity Inducers DOI Creative Commons
Nir London

Chemical Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 18, 2024

Molecules that are able to induce proximity between two proteins finding ever increasing applications in chemical biology and drug discovery. The ability introduce an electrophile make such inducers covalent can offer improved properties as selectivity, potency, duration of action, reduced molecular size. This concept has been heavily explored the context targeted degradation particular for bivalent molecules, but recently, additional reported other contexts, well monovalent glues. is a comprehensive review inducers, aiming identify common trends current gaps their discovery application.

Language: Английский

Citations

2