8PJI

MLLT1 in complex with compound 10a

Summary for 8PJI

• Entry DOI: 10.2210/pdb8pji/pdb
• Descriptor: Protein ENL, 1,2-ETHANEDIOL, DIMETHYL SULFOXIDE, ... (6 entities in total)
• Functional Keywords: complex inhibitor, peptide binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 18794.65

Authors

Raux, B.,Diaz-Saez, L.,Huber, K.V.M.,Fedorov, O.,Owen, D.R.,Londregan, A.T.,Bountra, C.,Edwards, A.,Arrowsmith, C. (deposition date: 2023-06-23, release date: 2023-11-22, Last modification date: 2023-12-27)

Primary citation

Raux, B.,Buchan, K.A.,Bennett, J.,Christott, T.,Dowling, M.S.,Farnie, G.,Fedorov, O.,Gamble, V.,Gileadi, C.,Giroud, C.,Huber, K.V.M.,Korczynska, M.,Limberakis, C.,Narayanan, A.,Owen, D.R.,Saez, L.D.,Stock, I.A.,Londregan, A.T.
Discovery of PFI-6, a small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3.
Bioorg.Med.Chem.Lett., 98:129546-129546, 2023

PubMed Abstract: 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.

PubMed: 37944866
DOI: 10.1016/j.bmcl.2023.129546

Experimental method

X-RAY DIFFRACTION (1.7 Å)