Discovery of PFI-6, a small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3

被引：3

作者：

Raux, Brigitt ^{[3
,4
]}

Buchan, Karly A. ^{[3
,4
]}

Bennett, James ^{[3
,4
]}

Christott, Thomas ^{[3
,4
]}

Dowling, Matthew S. ^{[2
]}

Farnie, Gillian ^{[3
]}

Fedorov, Oleg ^{[3
,4
]}

Gamble, Vicki ^{[3
]}

Gileadi, Carina ^{[3
]}

Giroud, Charline ^{[3
,4
]}

Huber, Kilian V. M. ^{[3
,4
]}

Korczynska, Magdalena ^{[1
]}

Limberakis, Chris ^{[2
]}

Narayanan, Arjun ^{[1
]}

Owen, Dafydd R. ^{[1
]}

Saez, Laura Diaz ^{[3
,4
]}

Stock, Ingrid A. ^{[2
]}

Londregan, Allyn T. ^{[1
]}

机构：

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

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

[3] Univ Oxford, Nuffield Dept Med, Ctr Med Discovery, Oxford OX3 7FZ, England

[4] Univ Oxford, Target Discovery Inst, Nuffield Dept Med, Oxford OX3 7FZ, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2024年 / 98卷

关键词：

Chemical probe; MLLT1; MLLT3; YEATS domain; Crystallography; LINKS HISTONE ACETYLATION; PHD FINGER; CROTONYLATION; TRANSCRIPTION; RECOGNITION; BROMODOMAIN; INHIBITORS; LANDSCAPE; READER; TARGET;

D O I：

10.1016/j.bmcl.2023.129546

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Epigenetic proteins containing YEATS domains (YD) are an emerging target class in drug discovery. Described herein are the discovery and characterization efforts associated with PFI-6, a new chemical probe for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). For hit identification, fragment-like mimetics of endogenous YD ligands (crotonylated histone-containing proteins), were synthesized via parallel medicinal chemistry (PMC) and screened for MLLT1 binding. Subsequent SAR studies led to iterative MLLT1/3 binding and selectivity improvements, culminating in the discovery of PFI-6. PFI-6 demonstrates good affinity and selectivity for MLLT1/3 vs. other human YD proteins (YEATS2/4) and engages MLLT3 in cells. Small-molecule X-ray co-crystal structures of two molecules, including PFI-6, bound to the YD of MLLT1/3 are also described. PFI-6 may be a useful tool molecule to better understand the biological effects associated with modulation of MLLT1/3.

引用

页数：7

共 28 条

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