蛋白激酶是疾病驱动因素，其治疗目标传统上集中于抑制酶活性。这里利用化学诱导的接近将激酶抑制剂转化为治疗基因的特定环境激活剂。开发了将转录因子 B 细胞淋巴瘤 6 (BCL6) 的配体与细胞周期蛋白依赖性激酶 (CDK) 的 ATP 竞争性抑制剂 (CDK) 连接起来的二价分子，以将 CDK 重新定位到染色质上的 BCL6 结合位点并直接磷酸化 RNA Pol二.由此产生的 BCL6 靶促凋亡基因表达转化为在 72 小时内杀死弥漫性大 B 细胞淋巴瘤 (DLBCL) 细胞，EC50 为 0.9 - 10 nM，并且高度特异性地消除小鼠中 BCL6 调节的生发中心反应。这些分子在正常淋巴细胞中的细胞毒性降低了 10,000 倍，并且在小鼠中具有良好的耐受性。基因组和蛋白质组证据证实了一种功能获得机制，其中不是全局酶抑制，而是总激酶活性的一部分被借用并重新定位到 BCL6 结合位点。该策略展示了如何使用激酶抑制剂来特定情况下激活转录，从而进入新的治疗空间。

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.