| Texto completo | |
| Autor(es): Mostrar menos - |
Pytel, Wiktoria A.
;
Patel, Urvashi
;
Smalley, Joshua P.
;
Millard, Christopher J.
;
Brown, Edward A.
;
Pavan, Aline R.
;
Wang, Siyu
;
Kalin, Jay H.
;
dos Santos, Jean Leandro
;
Cole, Philip A.
;
Hodgkinson, James T.
;
Schwabe, John W. R.
Número total de Autores: 12
|
| Tipo de documento: | Artigo Científico |
| Fonte: | Journal of the American Chemical Society; v. 147, n. 40, p. 9-pg., 2025-09-25. |
| Resumo | |
Class I histone deacetylases regulate gene transcription and are established therapeutic targets. HDAC1-3 form the catalytic subunit in several distinct multiprotein complexes; however, HDAC inhibitors are rarely studied in the context of these complexes. We evaluated multiple inhibitors, using seven HDAC complexes, and found that the inhibition profiles were highly complex-dependent, despite targeting the same enzyme. We also investigated the effect of the allosteric regulator inositol phosphate on these inhibitors. We observed very large, complex-selective reductions in the potency of benzamides bearing a "foot-pocket group", proposed to be selective for HDAC1/2. The potencies of these compounds are likely to be profoundly different in vivo compared with in vitro potencies in the absence of inositol phosphates. Our findings are supported by cell-based assays evaluating histone acetylation and HDAC degradation, highlighting the importance of evaluating HDACi in the context of HDAC complexes and inositol phosphates. (AU) | |
| Processo FAPESP: | 23/05739-6 - Estratégias para intervenção em complexos repressores do gene de gama-globina contendo Histona Deacetilase (HDAC-1 e HDAC-2) |
| Beneficiário: | Jean Leandro dos Santos |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 21/10059-9 - Síntese e avaliação farmacológica de compostos PROTAC baseados em inibidores de HDAC para anemia falciforme |
| Beneficiário: | Aline Renata Pavan |
| Modalidade de apoio: | Bolsas no Exterior - Estágio de Pesquisa - Doutorado |