7JUO

CBP bromodomain complexed with YF2-23

7JUO の概要

• エントリーDOI: 10.2210/pdb7juo/pdb
• 分子名称: CREB-binding protein, N-{1-[1,1-di(pyridin-2-yl)ethyl]-6-(1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-1H-indol-4-yl}ethanesulfonamide (3 entities in total)
• 機能のキーワード: dual bet/cbp inhibitor, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 116357.26

構造登録者

Ratia, K.M.,Xiong, R.,Principe, D.,Li, Y.,Huang, F.,Rana, A.,Thatcher, G. (登録日: 2020-08-20, 公開日: 2021-09-01, 最終更新日: 2023-10-18)

主引用文献

Principe, D.R.,Xiong, R.,Li, Y.,Pham, T.N.D.,Kamath, S.D.,Dubrovskyi, O.,Ratia, K.,Huang, F.,Zhao, J.,Shen, Z.,Thummuri, D.,Daohong, Z.,Underwood, P.W.,Trevino, J.,Munshi, H.G.,Thatcher, G.R.J.,Rana, A.
XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer.
Proc.Natl.Acad.Sci.USA, 119:-, 2022

PubMed Abstract: Pancreatic ductal adenocarcinoma (PDAC) is associated with extensive dysregulation of the epigenome and epigenetic regulators, such as bromodomain and extraterminal motif (BET) proteins, have been suggested as potential targets for therapy. However, single-agent BET inhibition has shown poor efficacy in clinical trials, and no epigenetic approaches are currently used in PDAC. To circumvent the limitations of the current generation of BET inhibitors, we developed the compound XP-524 as an inhibitor of the BET protein BRD4 and the histone acetyltransferase EP300/CBP, both of which are ubiquitously expressed in PDAC tissues and cooperate to enhance tumorigenesis. XP-524 showed increased potency and superior tumoricidal activity than the benchmark BET inhibitor JQ-1 in vitro, with comparable efficacy to higher-dose JQ-1 combined with the EP300/CBP inhibitor SGC-CBP30. We determined that this is in part due to the epigenetic silencing of KRAS in vitro, with similar results observed using ex vivo slice cultures of human PDAC tumors. Accordingly, XP-524 prevented KRAS-induced, neoplastic transformation in vivo and extended survival in two transgenic mouse models of aggressive PDAC. In addition to the inhibition of KRAS/MAPK signaling, XP-524 also enhanced the presentation of self-peptide and tumor recruitment of cytotoxic T lymphocytes, though these lymphocytes remained refractory from full activation. We, therefore, combined XP-524 with an anti-PD-1 antibody in vivo, which reactivated the cytotoxic immune program and extended survival well beyond XP-524 in monotherapy. Pending a comprehensive safety evaluation, these results suggest that XP-524 may benefit PDAC patients and warrant further exploration, particularly in combination with immune checkpoint inhibition.

PubMed: 35064087
DOI: 10.1073/pnas.2116764119

実験手法

X-RAY DIFFRACTION (2.2 Å)