2026-08-19 スタンフォード大学
＜関連情報＞
- https://news.stanford.edu/stories/2026/08/molecular-glue-lymphoma-cancer-driver-research
- https://www.sciencedirect.com/science/article/abs/pii/S0092867426007579
リジンアセチルトランスフェラーゼと癌遺伝子誘導性細胞死を連結する二価分子接着剤 A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death
Meredith N. Nix, Sai Gourisankar, Kevin J. Bowman, Sabin A. Nettles, Haopeng Yang, Brendan G. Dwyer, Roman C. Sarott, Hind Abuzaid, Michael M. Martinez, Nick Phillips, Vincent Cabaud, Artur Hakobyan, Vahram Arakelov, Garik Petrosyan, Aram Davtyan, Yanlan Wang, Juste M. Simanauskaite, Bryan A. Romero, Hannah M. Jones, Andrey Krokhotin …Gerald R. Crabtree
Cell Available online: 20 July 2026
DOI:https://doi.org/10.1016/j.cell.2026.06.037
Highlights
- Small-molecule-induced proximity between KATs and BCL6 elicits malignant cell death
- Fortuitous protein-protein contacts at complex interfaces enhance TCIP3 activity
- Fractional redirection of p300/CBP to BCL6 reprograms lymphoma epigenetic signaling
- Chemically induced proximity kills BCL6-driven lymphoma cells and tumors in vivo
Summary
Developing cancer therapies that induce specific death of malignant cells is critical for preventing relapse. Highly effective strategies, such as immunotherapy, exemplify this principle. Here, we provide the mechanistic basis for a small-molecule approach that leverages chemically induced proximity (CIP) to kill diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma. We developed lysine acetyltransferase (KAT)-based TCIPs (transcriptional/epigenetic chemical inducers of proximity), or KAT-TCIPs, which redirect p300/CREB-binding protein (CBP) to activate cell-death networks repressed by the oncogenic driver BCL6. Our lead KAT-TCIP reprograms the epigenome to initiate apoptosis. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance protein-protein interactions may be exploited to confer the potency and selectivity of KAT-TCIPs. Thus, oncogenic drivers can be co-opted to activate robust cell death. Consistent with their gain-of-function mechanism, TCIPs recruiting different transcriptional activators—p300, BRD4, or CDK9—produce distinct genomic responses, suggesting specialized therapeutic uses.
