2. Academic Validation
  3. A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-induced Cell Death

A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-induced Cell Death

  • bioRxiv. 2025 Mar 17:2025.03.14.643404. doi: 10.1101/2025.03.14.643404.
Meredith N Nix 1 2,  Sai Gourisankar 1,  Roman C Sarott 1,  Brendan G Dwyer 1,  Sabin A Nettles 3,  Michael M Martinez 1,  Hind Abuzaid 3,  Haopeng Yang 4,  Yanlan Wang 3,  Juste M Simanauskaite 3,  Bryan A Romero 1,  Hannah M Jones 1,  Andrey Krokhotin 3,  Tara N Lowensohn 2,  Lei Chen 5,  Cara Low 1,  Mark M Davis 5,  Daniel Fernandez 6,  Tinghu Zhang 1,  Michael R Green 4,  Stephen M Hinshaw 1,  Nathanael S Gray 1,  Gerald R Crabtree 3 7
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.
  • 2 Department of Chemistry, Stanford University, Stanford, CA, USA.
  • 3 Department of Pathology, Stanford University, Stanford, CA, USA.
  • 4 Department of Lymphoma- & Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
  • 6 Macromolecular Structure, Nucleus at Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • 7 Department of Developmental Biology, Stanford University, Stanford, CA, USA.
PMID: 40166243 DOI: 10.1101/2025.03.14.643404
Abstract

Developing Cancer therapies that induce robust death of the malignant cell is critical to prevent relapse. Highly effective strategies, such as immunotherapy, exemplify this observation. Here we provide the structural and molecular underpinnings for an approach that leverages chemical induced proximity to produce specific cell killing of diffuse large B cell lymphoma, the most common non-Hodgkin's lymphoma. We develop KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic chemical inducers of proximity) that redirect p300 and CBP to activate programmed cell death genes normally repressed by the oncogenic driver, BCL6. Acute treatment rapidly reprograms the epigenome to initiate Apoptosis and repress c-Myc. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance interactions between the two proteins can be systematically exploited to produce the exquisite potency and selectivity of KAT-TCIPs. Thus, the malignant function of an oncogenic driver can be co-opted to activate robust cell death, with implications for precision epigenetic therapies.

Keywords

induced proximity; lymphoma; lysine acetyltransferases; transcription.

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