Borrowing Transcriptional Kinases to Activate Apoptosis

Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor B-cell lymphoma 6 (BCL6) to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) were developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of RNA Pol II. The resulting BCL6-target proapoptotic gene expression translated into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72 h with EC50s of 0.9 – 10 nM and highly specific ablation of the BCL6-regulated germinal center response in mice. The molecules exhibited 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborated a gain-of-function mechanism where, instead of global enzyme inhibition, a fraction of total kinase activity is borrowed and re-localized to BCL6-bound loci. The strategy demonstrates how kinase inhibitors can be used to context-specifically activate transcription, accessing new therapeutic space. ### Competing Interest Statement G.R.C. is a founder and scientific advisor for Foghorn Therapeutics and Shenandoah Therapeutics. N.S.G. is a founder, science advisory board member (SAB) and equity holder in Syros, C4, Allorion, Lighthorse, Voronoi, Inception, Matchpoint, CobroVentures, GSK, Shenandoah (board member), Larkspur (board member) and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield, Springworks, Interline and Sanofi. T.Z. is a scientific founder, equity holder and consultant of Matchpoint. M.R.G. reports research funding from Sanofi, Kite/Gilead, Abbvie and Allogene; consulting for Abbvie, Allogene and Bristol Myers Squibb; honoraria from Tessa Therapeutics, Monte Rosa Therapeutics and Daiichi Sankyo; and stock ownership of KDAc Therapeutics. Shenandoah has a license from Stanford for the TCIP technology that was invented by G.R.C., S.G., A.K., R.C.S., B.A.K., N.S.G., and T.Z. All other authors declare no competing interests.