Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML

The design of selective small-molecules is often stymied by similar ligand binding pockets. Here we report the first cyclin-dependent kinase 6 (CDK6) degrader, BSJ-03-123, that uses phthalimide-conjugation to exploit protein-interface determinants to achieve proteome-wide degradation selectivity. Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and coupling acute degradation with transcriptomics and phosphoproteomics enabled dynamic mapping of the immediate role of CDK6 in coordinating signaling and transcription. Overall design: RNA-seq of MV4-11 cells treated for 6h with the CDK4/6 inhibitor palbociclib or the CDK6-specific phthalimide conjugates BSJ-03-123 and YKL-06-102

选择性小分子的设计常受限于相似的配体结合口袋。本研究报道了首个细胞周期蛋白依赖性激酶6（cyclin-dependent kinase 6, CDK6）降解剂BSJ-03-123，该降解剂通过邻苯二甲酰亚胺缀合策略利用蛋白质界面决定簇，实现了全蛋白质组水平的降解选择性。药理学靶向的CDK6降解可作用于急性髓系白血病细胞的选择性依赖特性，将快速降解与转录组学、磷酸化蛋白质组学相结合，能够动态绘制CDK6在协调信号传导与转录过程中的即时作用。
总体实验设计：对经CDK4/6抑制剂帕博西尼（palbociclib）或CDK6特异性邻苯二甲酰亚胺缀合物BSJ-03-123、YKL-06-102处理6小时的MV4-11细胞进行RNA-seq分析。