Relocalizing transcriptional kinases to activate apoptosis.

Autor: Sarott RC; Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA., Gourisankar S; Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA., Karim B; Department of Chemistry, Stanford University, Stanford, CA 94305, USA., Nettles S; Department of Pathology, Stanford University, Stanford, CA 94305, USA., Yang H; Department of Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, TX 77030, USA., Dwyer BG; Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA., Simanauskaite JM; Department of Pathology, Stanford University, Stanford, CA 94305, USA., Tse J; Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA., Abuzaid H; Department of Pathology, Stanford University, Stanford, CA 94305, USA., Krokhotin A; Department of Pathology, Stanford University, Stanford, CA 94305, USA., Zhang T; Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA., Hinshaw SM; Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA., Green MR; Department of Lymphoma & Myeloma, MD Anderson Cancer Center, Houston, TX 77030, USA., Crabtree GR; Department of Pathology, Stanford University, Stanford, CA 94305, USA.; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA., Gray NS; Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2024 Oct 04; Vol. 386 (6717), pp. eadl5361. Date of Electronic Publication: 2024 Oct 04.
DOI: 10.1126/science.adl5361
Abstrakt: 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.
Databáze: MEDLINE
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