9IT5

p300 KAT domain in complex with KB528

This is a non-PDB format compatible entry.

Summary for 9IT5

• Entry DOI: 10.2210/pdb9it5/pdb
• Descriptor: Histone acetyltransferase p300, 4-[(2~{S})-1-[[(~{R})-[(3~{S})-7-(1-methylpyrazol-4-yl)-2,3-dihydro-1~{H}-pyrido[2,3-b][1,4]oxazin-3-yl]-phenyl-methyl]amino]propan-2-yl]benzenecarbonitrile, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: kb528, ep300, p300, histone acetyltransferase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 82092.74

Authors

Rahl, P.,Gao, H.,Calderon, Y.,Wang, Z.-F. (deposition date: 2024-07-19, release date: 2025-07-23, Last modification date: 2025-12-10)

Primary citation

Lenoir, W.F.,McKeown, M.R.,Giorgetti, G.,Kobylarz, M.J.,Hopkins, T.D.,Glore, W.L.,Shum, M.G.,Calderon, Y.,Encinas Mayoral, J.,Carvajal, L.A.,Mori, K.R.,Li, J.,Gao, H.,Zheng, Y.,Ma, Z.,Obholzer, N.D.,Zhou, M.,Trotter, B.W.,Dinsmore, C.J.,Munshi, N.C.,Lin, C.Y.,Fulciniti, M.,Rahl, P.B.
Catalytic Inhibition of p300 Preferentially Targets IRF4 Oncogenic Activity and Tumor Growth in Multiple Myeloma.
Cancer Res., 2025

PubMed Abstract: The oncogenic transcription factor (TF) IRF4 is a currently undrugged universal multiple myeloma (MM) dependency. Using transcriptional regulatory network (TRN) mapping, an unbiased multi-omic target ID approach, we identified the coactivator lysine acetyltransferase (KAT) p300 as a key IRF4 partner. Validation of this preferential relationship through quantitative interactome mapping revealed that IRF4 was the most abundant MM specific dependency and more closely complexed with p300 than other TFs, such as IKZF1/IKZF3. Development of optimized p300 lysine acetyltransferase (KAT) inhibitors enabled inhibition of IRF4 activity and MM proliferation ex vivo and in vivo. p300/CBP KAT inhibition preferentially targeted MM cells over normal cells, specifically modulating the MM transcriptome, and the p300 KAT inhibitors more completely inhibited IRF4 activity at lower levels compared to existing p300/CBP bromodomain inhibitors. Furthermore, combining p300/CBP KAT inhibition and therapeutics with orthogonal mechanisms targeting transcription in MM elicited synergistic anti-tumor effects. Together, these data motivate the ongoing clinical development of p300/CBP KAT inhibition in MM.

PubMed: 41248492
DOI: 10.1158/0008-5472.CAN-25-3440

Experimental method

X-RAY DIFFRACTION (2 Å)