7LJE

Discovery of Spirohydantoins as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases

Summary for 7LJE

• Entry DOI: 10.2210/pdb7lje/pdb
• Descriptor: Histone acetyltransferase p300, 2-[4-[(3'R,4S)-3'-fluoro-1-[2-[(4-fluorophenyl)methyl-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]amino]-2-oxo-ethyl]-2,5-dioxo-spiro[imidazolidine-4,1'-indane]-5'-yl]pyrazol-1-yl]-N-methyl-acetamide (3 entities in total)
• Functional Keywords: histone acetylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 163518.22

Authors

Jakob, C.G. (deposition date: 2021-01-29, release date: 2021-03-17, Last modification date: 2023-10-18)

Primary citation

Ji, Z.,Clark, R.F.,Bhat, V.,Matthew Hansen, T.,Lasko, L.M.,Bromberg, K.D.,Manaves, V.,Algire, M.,Martin, R.,Qiu, W.,Torrent, M.,Jakob, C.G.,Liu, H.,Cole, P.A.,Marmorstein, R.,Kesicki, E.A.,Lai, A.,Michaelides, M.R.
Discovery of spirohydantoins as selective, orally bioavailable inhibitors of p300/CBP histone acetyltransferases.
Bioorg.Med.Chem.Lett., 39:127854-127854, 2021

PubMed Abstract: p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.

PubMed: 33631370
DOI: 10.1016/j.bmcl.2021.127854

Experimental method

X-RAY DIFFRACTION (2.607 Å)