Samarasinghe Kusal T G, An Elvira, Genuth Miriam A, Chu Ling, Holley Scott A, Crews Craig M
Department of Molecular, Cellular & Developmental Biology, Yale University New Haven CT 06511 USA
Department of Pharmacology, Yale University New Haven CT 06511 USA.
RSC Chem Biol. 2022 Jul 26;3(9):1144-1153. doi: 10.1039/d2cb00138a. eCollection 2022 Aug 31.
Dysregulated transcription factors (TFs) that rewire gene expression circuitry are frequently identified as key players in disease. Although several TFs have been drugged with small molecules, the majority of oncogenic TFs are not currently pharmaceutically tractable due to their paucity of ligandable pockets. The first generation of transcription factor targeting chimeras (TRAFTACs) was developed to target TFs for proteasomal degradation by exploiting their DNA binding ability. In the current study, we have developed the second generation TRAFTACs ("oligoTRAFTACs") composed of a TF-binding oligonucleotide and an E3 ligase-recruiting ligand. Herein, we demonstrate the development of oligoTRAFTACs to induce the degradation of two oncogenic TFs, c-Myc and brachyury. In addition, we show that brachyury can be successfully degraded by oligoTRAFTACs in chordoma cell lines. Furthermore, zebrafish experiments demonstrate oligoTRAFTAC activity. Overall, our data demonstrate oligoTRAFTACs as a generalizable platform towards difficult-to-drug TFs and their degradability the proteasomal pathway.
失调的转录因子（TFs）会重新连接基因表达回路，它们常被视为疾病的关键因素。尽管已有几种转录因子能用小分子药物作用，但由于大多数致癌转录因子可成药口袋稀少，目前在药学上难以处理。第一代靶向转录因子嵌合体（TRAFTACs）是通过利用转录因子的DNA结合能力，将其靶向蛋白酶体降解而开发的。在本研究中，我们开发了第二代TRAFTACs（“寡聚TRAFTACs”），它由一个转录因子结合寡核苷酸和一个招募E3连接酶的配体组成。在此，我们展示了寡聚TRAFTACs的开发过程，以诱导两种致癌转录因子c-Myc和短尾型（brachyury）的降解。此外，我们表明寡聚TRAFTACs能在脊索瘤细胞系中成功降解短尾型。此外，斑马鱼实验证明了寡聚TRAFTACs的活性。总体而言，我们的数据表明寡聚TRAFTACs是针对难以成药的转录因子及其通过蛋白酶体途径降解性的一个通用平台。
