BibTex format
@article{Shah:2024:10.1021/acs.jmedchem.3c02123,
author = {Shah, R and De, Vita E and Sathyamurthi, P and Conole, D and Zhang, X and Fellows, E and Dickinson, E and Fleites, C and Queisser, M and Harling, J and Tate, E},
doi = {10.1021/acs.jmedchem.3c02123},
journal = {Journal of Medicinal Chemistry},
pages = {4641--4654},
title = {Structure-guided design and optimization of covalent VHL-targeted sulfonyl fluoride PROTACs},
url = {http://dx.doi.org/10.1021/acs.jmedchem.3c02123},
volume = {67},
year = {2024}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that have emerged as a therapeutic modality to induce targeted protein degradation (TPD) by harnessing cellular proteolytic degradation machinery. PROTACs which ligand the E3 ligase in a covalent manner have attracted intense interest, however, covalent PROTACs with a broad protein of interest (POI) scope have proven challenging to discover by design. Here, we report structure-guided design and optimization of Von Hippel-Lindau (VHL) protein-targeted sulfonyl fluorides which covalently bind Ser110 in the HIF1α binding site. We demonstrate that their incorporation in bifunctional degraders induces targeted protein degradation of BRD4 or androgen receptor (AR) without further linker optimization. Our study discloses the first covalent VHL ligands which can be implemented directly in bifunctional degrader design expanding the substrate scope of covalent E3 ligase PROTACs.
AU - Shah,R
AU - De,Vita E
AU - Sathyamurthi,P
AU - Conole,D
AU - Zhang,X
AU - Fellows,E
AU - Dickinson,E
AU - Fleites,C
AU - Queisser,M
AU - Harling,J
AU - Tate,E
DO - 10.1021/acs.jmedchem.3c02123
EP - 4654
PY - 2024///
SN - 0022-2623
SP - 4641
TI - Structure-guided design and optimization of covalent VHL-targeted sulfonyl fluoride PROTACs
T2 - Journal of Medicinal Chemistry
UR - http://dx.doi.org/10.1021/acs.jmedchem.3c02123
UR - https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c02123
UR - http://hdl.handle.net/10044/1/109215
VL - 67
ER -
