9IT5

p300 KAT domain in complex with KB528

これはPDB形式変換不可エントリーです。

9IT5 の概要

• エントリーDOI: 10.2210/pdb9it5/pdb
• 分子名称: 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)
• 機能のキーワード: kb528, ep300, p300, histone acetyltransferase, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82092.74

構造登録者

Rahl, P.,Gao, H.,Calderon, Y.,Wang, Z.-F. (登録日: 2024-07-19, 公開日: 2025-07-23, 最終更新日: 2026-03-04)

主引用文献

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., 86:1010-1034, 2026

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

実験手法

X-RAY DIFFRACTION (2 Å)