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

被引：12

作者：

Londregan, Allyn T. ^{[1
]}

Aitmakhanova, Karlygash ^{[2
]}

Bennett, James ^{[2
]}

Byrnes, Laura J. ^{[3
]}

Canterbury, Daniel P. ^{[3
]}

Cheng, Xiayun ^{[3
]}

Christott, Thomas ^{[2
]}

Clemens, Jennifer ^{[3
]}

Coffey, Steven B. ^{[3
]}

Dias, Joao M. ^{[3
]}

Dowling, Matthew S. ^{[3
]}

Farnie, Gillian ^{[2
]}

Fedorov, Oleg ^{[2
]}

Fennell, Kimberly F. ^{[3
]}

Gamble, Vicki ^{[2
]}

Gileadi, Carina ^{[2
]}

Giroud, Charline ^{[2
]}

Harris, Michael R. ^{[3
]}

Hollingshead, Brett D. ^{[3
]}

Huber, Kilian ^{[2
]}

Korczynska, Magdalena ^{[3
]}

Lapham, Kimberly ^{[1
,3
]}

Loria, Paula M. ^{[3
]}

Narayanan, Arjun ^{[4
]}

Owen, Dafydd R. . ^{[4
]}

Raux, Brigitt ^{[2
]}

Sahasrabudhe, Parag, V ^{[3
]}

Ruggeri, Roger B. ^{[3
]}

Saez, Laura Diaz ^{[2
]}

Stock, Ingrid A. . ^{[3
]}

Thuma, Benjamin A. . ^{[3
]}

Tsai, Andy ^{[3
]}

Varghese, Alison E. ^{[3
]}

机构：

[1] Pfizer Med Design, Pfizer Worldwide Res & Dev, Cambridge, MA 02139 USA

[2] Univ Oxford, Ctr Med Discovery, NDM, Oxford OX37DQ, Oxon, England

[3] Pfizer Worldwide Res & Dev, Groton, CT 06340 USA

[4] Pfizer Worldwide Res & Dev, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 01期

关键词：

LINKS HISTONE ACETYLATION; PHD FINGER; CELL-PROLIFERATION; DOMAIN; TRANSCRIPTION; RECOGNITION; PROMOTES; CANCER; GAS41; CROTONYLATION;

D O I：

10.1021/acs.jmedchem.2c01421

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 vivocapable binders.

引用

页码：460 / 472

页数：13

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