Matches in SemOpenAlex for { <https://semopenalex.org/work/W4387492209> ?p ?o ?g. }
- W4387492209 abstract "Abstract The Src homology 2 (SH2) domain recognizes phosphotyrosine (pY) post translational modifications in partner proteins to trigger downstream signaling. Drug discovery efforts targeting the SH2 domains have long been stymied by the poor drug-like properties of phosphate and its mimetics. Here, we use structure-based design to target the SH2 domain of the E3 ligase suppressor of cytokine signaling 2 (SOCS2). Starting from the highly ligand-efficient pY amino acid, a fragment growing approach reveals covalent modification of Cys111 in a co-crystal structure, which we leverage to rationally design a cysteine-directed electrophilic covalent inhibitor MN551. We report the prodrug MN714 containing a pivaloyloxymethyl (POM) protecting group and evidence its cell permeability and capping group unmasking using cellular target engagement and in-cell 19 F NMR spectroscopy. Covalent engagement at Cys111 competitively blocks recruitment of cellular SOCS2 protein to its native substrate. The qualified inhibitors of SOCS2 could find attractive applications as chemical probes to understand the biology of SOCS2 and its CRL5 complex, and as E3 ligase handles in proteolysis targeting chimera (PROTACs) to induce targeted protein degradation." @default.
- W4387492209 created "2023-10-11" @default.
- W4387492209 creator A5014084221 @default.
- W4387492209 creator A5014356147 @default.
- W4387492209 creator A5021890635 @default.
- W4387492209 creator A5035167260 @default.
- W4387492209 creator A5036373931 @default.
- W4387492209 creator A5058594295 @default.
- W4387492209 creator A5061968220 @default.
- W4387492209 creator A5070854711 @default.
- W4387492209 creator A5079763052 @default.
- W4387492209 creator A5084090963 @default.
- W4387492209 creator A5092649049 @default.
- W4387492209 date "2023-10-10" @default.
- W4387492209 modified "2023-10-14" @default.
- W4387492209 title "Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2" @default.
- W4387492209 cites W1600880434 @default.
- W4387492209 cites W1982052532 @default.
- W4387492209 cites W1984803306 @default.
- W4387492209 cites W1997952190 @default.
- W4387492209 cites W1999030981 @default.
- W4387492209 cites W2008525757 @default.
- W4387492209 cites W2008969748 @default.
- W4387492209 cites W2022008947 @default.
- W4387492209 cites W2030849371 @default.
- W4387492209 cites W2038542011 @default.
- W4387492209 cites W2041053673 @default.
- W4387492209 cites W2059692439 @default.
- W4387492209 cites W2065136554 @default.
- W4387492209 cites W2068944159 @default.
- W4387492209 cites W2073220467 @default.
- W4387492209 cites W2096498130 @default.
- W4387492209 cites W2098167941 @default.
- W4387492209 cites W2102830593 @default.
- W4387492209 cites W2110808180 @default.
- W4387492209 cites W2112582144 @default.
- W4387492209 cites W2114335223 @default.
- W4387492209 cites W2114367386 @default.
- W4387492209 cites W2114731575 @default.
- W4387492209 cites W2120772351 @default.
- W4387492209 cites W2127322768 @default.
- W4387492209 cites W2130839034 @default.
- W4387492209 cites W2143660875 @default.
- W4387492209 cites W2144081223 @default.
- W4387492209 cites W2145501898 @default.
- W4387492209 cites W2161413435 @default.
- W4387492209 cites W22382808 @default.
- W4387492209 cites W2287686703 @default.
- W4387492209 cites W2337956242 @default.
- W4387492209 cites W2527718275 @default.
- W4387492209 cites W2546637348 @default.
- W4387492209 cites W2590187755 @default.
- W4387492209 cites W2607978828 @default.
- W4387492209 cites W2751709490 @default.
- W4387492209 cites W2774816960 @default.
- W4387492209 cites W2793311671 @default.
- W4387492209 cites W2802907023 @default.
- W4387492209 cites W2808681120 @default.
- W4387492209 cites W2899765925 @default.
- W4387492209 cites W2900884817 @default.
- W4387492209 cites W2901459245 @default.
- W4387492209 cites W2910064809 @default.
- W4387492209 cites W2936890006 @default.
- W4387492209 cites W2973457155 @default.
- W4387492209 cites W2983066254 @default.
- W4387492209 cites W2986817448 @default.
- W4387492209 cites W2990159340 @default.
- W4387492209 cites W3009475840 @default.
- W4387492209 cites W3018180387 @default.
- W4387492209 cites W3021210206 @default.
- W4387492209 cites W3045530700 @default.
- W4387492209 cites W3081357927 @default.
- W4387492209 cites W3093320111 @default.
- W4387492209 cites W3109429946 @default.
- W4387492209 cites W3188946293 @default.
- W4387492209 cites W3210775796 @default.
- W4387492209 cites W3216323749 @default.
- W4387492209 cites W4200489509 @default.
- W4387492209 cites W4205379795 @default.
- W4387492209 cites W4210675630 @default.
- W4387492209 cites W4248872320 @default.
- W4387492209 cites W4280618938 @default.
- W4387492209 cites W4308099893 @default.
- W4387492209 cites W4311833295 @default.
- W4387492209 cites W4367174593 @default.
- W4387492209 doi "https://doi.org/10.1038/s41467-023-41894-3" @default.
- W4387492209 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37816714" @default.
- W4387492209 hasPublicationYear "2023" @default.
- W4387492209 type Work @default.
- W4387492209 citedByCount "0" @default.
- W4387492209 crossrefType "journal-article" @default.
- W4387492209 hasAuthorship W4387492209A5014084221 @default.
- W4387492209 hasAuthorship W4387492209A5014356147 @default.
- W4387492209 hasAuthorship W4387492209A5021890635 @default.
- W4387492209 hasAuthorship W4387492209A5035167260 @default.
- W4387492209 hasAuthorship W4387492209A5036373931 @default.
- W4387492209 hasAuthorship W4387492209A5058594295 @default.
- W4387492209 hasAuthorship W4387492209A5061968220 @default.
- W4387492209 hasAuthorship W4387492209A5070854711 @default.
- W4387492209 hasAuthorship W4387492209A5079763052 @default.