Cell, Molecular and Developmental Biology Program, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, United States.
Department of Chemistry, Tufts University, Medford, MA 02155, United States.
Bioorg Med Chem. 2020 Jun 15;28(12):115542. doi: 10.1016/j.bmc.2020.115542. Epub 2020 May 4.
The signal transducer and activator of transcription 3 (STAT3) protein is constitutively activated in several cancers. STAT3 activity can be blocked by inhibiting its Src Homology 2 (SH2) domain, but phosphotyrosine and its isosteres have poor bioavailability. In this work, we develop peptide-based inhibitors of STAT3-SH2 by combining chemical strategies that have proven effective for targeting other SH2 domains. These strategies include a STAT3-specific selectivity sequence, non-hydrolyzable phosphotyrosine isosteres, and a high-efficiency cell-penetrating peptide. Peptides that combined these three strategies had substantial biological stability and cytosolic delivery, as measured using highly quantitative cell-based assays. However, these peptides did not inhibit STAT3 activity in cells. By comparing in vitro binding affinity, cell penetration, and proteolytic stability, this work explores the delicate balance of factors that contribute to biological activity for peptidic inhibitors of STAT3.
信号转导子和转录激活子 3（STAT3）蛋白在几种癌症中持续激活。STAT3 的活性可以通过抑制其Src 同源性 2（SH2）结构域来阻断，但是磷酸酪氨酸及其类似物的生物利用度较差。在这项工作中，我们通过结合已被证明对其他 SH2 结构域有效的化学策略，开发了针对 STAT3-SH2 的基于肽的抑制剂。这些策略包括 STAT3 特异性选择性序列、不可水解的磷酸酪氨酸类似物和高效的细胞穿透肽。使用高度定量的基于细胞的测定法，组合了这三种策略的肽具有很大的生物稳定性和细胞质递送。然而，这些肽并不能抑制细胞中的 STAT3 活性。通过比较体外结合亲和力、细胞穿透性和蛋白水解稳定性，这项工作探讨了影响 STAT3 肽类抑制剂生物学活性的各种因素之间的微妙平衡。
