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

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.

doi:10.1021/acs.jmedchem.2c01421.s001

jm2c01421_si_001.pdf (1.5 MB)

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

journal contribution

posted on 2022-12-23, 16:35 authored by Allyn T. Londregan, Karlygash Aitmakhanova, James Bennett, Laura J. Byrnes, Daniel P. Canterbury, Xiayun Cheng, Thomas Christott, Jennifer Clemens, Steven B. Coffey, João M. Dias, Matthew S. Dowling, Gillian Farnie, Oleg Fedorov, Kimberly F. Fennell, Vicki Gamble, Carina Gileadi, Charline Giroud, Michael R. Harris, Brett D. Hollingshead, Kilian Huber, Magdalena Korczynska, Kimberly Lapham, Paula M. Loria, Arjun Narayanan, Dafydd R. Owen, Brigitt Raux, Parag V. Sahasrabudhe, Roger B. Ruggeri, Laura Díaz Sáez, Ingrid A. Stock, Benjamin A. Thuma, Andy Tsai, Alison E. Varghese

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.