Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
Science. 2024 Oct 4;386(6717):eadl5361. doi: 10.1126/science.adl5361.
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.
激酶是细胞功能的关键调节因子，它们通常与疾病的发生机制有关。大多数靶向激酶的药物都是抑制其催化活性的分子，但在这里，我们使用化学诱导接近将激酶抑制剂转化为治疗基因的激活剂。我们合成了双价分子，将转录因子 B 细胞淋巴瘤 6 (BCL6) 的配体与细胞周期蛋白依赖性激酶 (CDKs) 的抑制剂连接起来。这些分子将 CDK9 重新定位到 BCL6 结合的 DNA 上，并指导 RNA 聚合酶 II 的磷酸化。由此产生的促凋亡、BCL6 靶基因的表达导致弥漫性大 B 细胞淋巴瘤细胞的杀伤和 BCL6 调节的生发中心反应的特异性消融。基因组学和蛋白质组学证实了一种获得性功能机制，其中并非全局激酶活性被抑制，而是被重新定向。因此，激酶抑制剂可用于特定于上下文的转录激活。
