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

共 52 条

[1] THE PHD FINGER - IMPLICATIONS FOR CHROMATIN-MEDIATED TRANSCRIPTIONAL REGULATION
AASLAND, R
GIBSON, TJ
STEWART, AF
[J]. TRENDS IN BIOCHEMICAL SCIENCES, 1995, 20 (02) : 56 - 59
[2] [Anonymous], 2015, Molecular Operating Environment (MOE)
[3] Cell-Based Ligand Discovery for the ENL YEATS Domain
Asiaban, Joshua N.
Milosevich, Natalia
Chen, Emily
Bishop, Timothy R.
Wang, Justin
Zhang, Yuxiang
Ackerman, Christopher J.
Hampton, Eric N.
Young, Travis S.
Hull, Mitchell V.
Cravatt, Benjamin F.
Erb, Michael A.
[J]. ACS CHEMICAL BIOLOGY, 2020, 15 (04) : 895 - 903
[4] The PHD finger, a nuclear protein-interaction domain
Bienz, M
[J]. TRENDS IN BIOCHEMICAL SCIENCES, 2006, 31 (01) : 35 - 40
[5] YEATS4 promotes the tumorigenesis of pancreatic cancer by activating beta-catenin/TCF signaling
Chen Jixiang
Dang Shengchun
Qu Jianguo
Mao Zhengfa
Fan Xin
Wang Xuqing
Zhang Jianxin
Cui Lei
[J]. ONCOTARGET, 2017, 8 (15) : 25200 - 25210
[6] A physiological model of granulopoiesis to predict clinical drug induced neutropenia from in vitro bone marrow studies: with application to a cell cycle inhibitor
Chen, Wenbo
Boras, Britton
Sung, Tae
Yu, Yanke
Zheng, Jenny
Wang, Diane
Hu, Wenyue
Spilker, Mary E.
D'Argenio, David Z.
[J]. JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, 2020, 47 (02) : 163 - 182
[7] Discovery of a Selective Inhibitor for the YEATS Domains of ENL/AF9
Christott, Thomas
Bennett, James
Coxon, Carmen
Monteiro, Octovia
Giroud, Charline
Beke, Viktor
Felce, Suet Ling
Gamble, Vicki
Gileadi, Carina
Poda, Gennady
Al-awar, Rima
Farnie, Gillian
Fedorov, Oleg
[J]. SLAS DISCOVERY, 2019, 24 (02) : 133 - 141
[8] Structure and ligand of a histone acetyltransferase bromodomain
Dhalluin, C
Carlson, JE
Zeng, L
He, C
Aggarwal, AK
Zhou, MM
[J]. NATURE, 1999, 399 (6735) : 491 - 496
[9] Transcription control by the ENL YEATS domain in acute leukaemia
Erb, Michael A.
Scott, Thomas G.
Li, Bin E.
Xie, Huafeng
Paulk, Joshiawa
Seo, Hyuk-Soo
Souza, Amanda
Roberts, Justin M.
Dastjerdi, Shiva
Buckley, Dennis L.
Sanjana, Neville E.
Shalem, Ophir
Nabet, Behnam
Zeid, Rhamy
Offei-Addo, Nana K.
Dhe-Paganon, Sirano
Zhang, Feng
Orkin, Stuart H.
Winter, Georg E.
Bradner, James E.
[J]. NATURE, 2017, 543 (7644) : 270 - +
[10] Faller Christina E, 2015, Methods Mol Biol, V1289, P75, DOI 10.1007/978-1-4939-2486-8_7

← 1 2 3 4 5 6 →