Discovery of PFI-6, a small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3
Copyright © 2023 Elsevier Ltd. All rights reserved..
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.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:98 |
---|---|
Enthalten in: |
Bioorganic & medicinal chemistry letters - 98(2024) vom: 15. Jan., Seite 129546 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Raux, Brigitt [VerfasserIn] |
---|
Links: |
---|
Themen: |
Chemical probe |
---|
Anmerkungen: |
Date Completed 10.01.2024 Date Revised 10.01.2024 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1016/j.bmcl.2023.129546 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM36436579X |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM36436579X | ||
003 | DE-627 | ||
005 | 20240114233413.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1016/j.bmcl.2023.129546 |2 doi | |
028 | 5 | 2 | |a pubmed24n1255.xml |
035 | |a (DE-627)NLM36436579X | ||
035 | |a (NLM)37944866 | ||
035 | |a (PII)S0960-894X(23)00424-9 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Raux, Brigitt |e verfasserin |4 aut | |
245 | 1 | 0 | |a Discovery of PFI-6, a small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3 |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 10.01.2024 | ||
500 | |a Date Revised 10.01.2024 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Copyright © 2023 Elsevier Ltd. All rights reserved. | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Chemical probe | |
650 | 4 | |a Crystallography | |
650 | 4 | |a MLLT1 | |
650 | 4 | |a MLLT3 | |
650 | 4 | |a YEATS domain | |
650 | 7 | |a Nuclear Proteins |2 NLM | |
650 | 7 | |a Histones |2 NLM | |
650 | 7 | |a MLLT1 protein, human |2 NLM | |
650 | 7 | |a Neoplasm Proteins |2 NLM | |
650 | 7 | |a Transcription Factors |2 NLM | |
650 | 7 | |a MLLT3 protein, human |2 NLM | |
700 | 1 | |a Buchan, Karly A |e verfasserin |4 aut | |
700 | 1 | |a Bennett, James |e verfasserin |4 aut | |
700 | 1 | |a Christott, Thomas |e verfasserin |4 aut | |
700 | 1 | |a Dowling, Matthew S |e verfasserin |4 aut | |
700 | 1 | |a Farnie, Gillian |e verfasserin |4 aut | |
700 | 1 | |a Fedorov, Oleg |e verfasserin |4 aut | |
700 | 1 | |a Gamble, Vicki |e verfasserin |4 aut | |
700 | 1 | |a Gileadi, Carina |e verfasserin |4 aut | |
700 | 1 | |a Giroud, Charline |e verfasserin |4 aut | |
700 | 1 | |a Huber, Kilian V M |e verfasserin |4 aut | |
700 | 1 | |a Korczynska, Magdalena |e verfasserin |4 aut | |
700 | 1 | |a Limberakis, Chris |e verfasserin |4 aut | |
700 | 1 | |a Narayanan, Arjun |e verfasserin |4 aut | |
700 | 1 | |a Owen, Dafydd R |e verfasserin |4 aut | |
700 | 1 | |a Sáez, Laura Díaz |e verfasserin |4 aut | |
700 | 1 | |a Stock, Ingrid A |e verfasserin |4 aut | |
700 | 1 | |a Londregan, Allyn T |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Bioorganic & medicinal chemistry letters |d 1992 |g 98(2024) vom: 15. Jan., Seite 129546 |w (DE-627)NLM09063828X |x 1464-3405 |7 nnns |
773 | 1 | 8 | |g volume:98 |g year:2024 |g day:15 |g month:01 |g pages:129546 |
856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bmcl.2023.129546 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 98 |j 2024 |b 15 |c 01 |h 129546 |