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.
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页数：7
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