Relocalizing transcriptional kinases to activate apoptosis
Kinases are critical regulators of cellular function that are commonly implicated in the mechanisms underlying disease. Most drugs that target kinases are molecules that inhibit their catalytic activity, but here we used chemically induced proximity to convert kinase inhibitors into activators of therapeutic genes. We synthesized bivalent molecules that link ligands of the transcription factor B cell lymphoma 6 (BCL6) to inhibitors of cyclin-dependent kinases (CDKs). These molecules relocalized CDK9 to BCL6-bound DNA and directed phosphorylation of RNA polymerase II. The resulting expression of pro-apoptotic, BCL6-target genes caused killing of diffuse large B cell lymphoma cells and specific ablation of the BCL6-regulated germinal center response. Genomics and proteomics corroborated a gain-of-function mechanism in which global kinase activity was not inhibited but rather redirected. Thus, kinase inhibitors can be used to context-specifically activate transcription.
Authors
- Juste Simanauskaite (ORCID: https://orcid.org/0009-0009-1385-2599)
- Stephen M. Hinshaw (ORCID: https://orcid.org/0000-0003-4215-5206)
- Nathanael S. Gray (ORCID: https://orcid.org/0000-0001-5354-7403)
- Brendan G. Dwyer (ORCID: https://orcid.org/0000-0001-8593-4184)
- Haopeng Yang (ORCID: https://orcid.org/0000-0002-3870-2679)
- Jason Tse (ORCID: https://orcid.org/0000-0002-6958-0256)
- Basel A. Karim (ORCID: https://orcid.org/0000-0002-7928-0433)
- Sabin A. Nettles (ORCID: https://orcid.org/0000-0002-1913-9016)
- Sai Gourisankar (ORCID: https://orcid.org/0000-0003-0132-8086)
- Michael Richard Green (ORCID: https://orcid.org/0000-0001-6309-9472)
- Roman C. Sarott (ORCID: https://orcid.org/0000-0001-8789-6150)
- Gerald R. Crabtree (ORCID: https://orcid.org/0000-0001-9685-7911)
- Hind Abuzaid (ORCID: https://orcid.org/0000-0002-5454-7672)
- Tinghu Zhang (ORCID: https://orcid.org/0000-0003-1028-8020)
- A. Krokhotin (ORCID: https://orcid.org/0009-0006-4435-3213)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Stanford University (US)
Publication Details
- Journal
- Science
- Published
- 2024-10-03
- DOI
- https://doi.org/10.1126/science.adl5361
- Citations
- 52
- Primary Topic
- Cancer-related Molecular Pathways
- Type
- article
- Field-Weighted Citation Impact
- 14.69
Funders
- National Science Foundation
- Sanofi
- Springworks Therapeutics
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Astellas Pharma
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- Stanford Cancer Institute
- Moonshot Research and Development Program