Details

Autor(en) / Beteiligte

• Londregan, Allyn T.
• Aitmakhanova, Karlygash
• Bennett, James
• Byrnes, Laura J.
• Canterbury, Daniel P.
• Cheng, Xiayun
• Christott, Thomas
• Clemens, Jennifer
• Coffey, Steven B.
• Dias, João M.
• Dowling, Matthew S.
• Farnie, Gillian
• Fedorov, Oleg
• Fennell, Kimberly F.
• Gamble, Vicki
• Gileadi, Carina
• Giroud, Charline
• Harris, Michael R.
• Hollingshead, Brett D.
• Huber, Kilian
• Korczynska, Magdalena
• Lapham, Kimberly
• Loria, Paula M.
• Narayanan, Arjun
• Owen, Dafydd R.
• Raux, Brigitt
• Sahasrabudhe, Parag V.
• Ruggeri, Roger B.
• Sáez, Laura Díaz
• Stock, Ingrid A.
• Thuma, Benjamin A.
• Tsai, Andy
• Varghese, Alison E.

Titel

Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4

Ist Teil von

• Journal of medicinal chemistry, 2023-01, Vol.66 (1), p.460-472

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• A series of small-molecule YEATS4 binders have been discovered as part of an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such as 4d and 4e demonstrate excellent potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit good physical properties and in vitro safety profiles. A new X-ray crystal structure confirms direct binding of this chemical series to YEATS4 at the lysine acetylation recognition site of the YEATS domain. Multiple analogues engage YEATS4 with nanomolar potency in a whole-cell nanoluciferase bioluminescent resonance energy transfer assay. Rodent pharmacokinetic studies demonstrate the competency of several analogues as in vivo-capable binders.