Peptides for specific inhibition of Jag1-Notch1 pathway

Abstract

Aberrant cross talk between Notch ligand (e.g. Jag1) and Notch receptor (e.g. Notch 1) has been implicated in tumorigenesis in the colon. Inhibition of Notch pathway is therefore an attractive approach for treating diseases with upregulated Jagl e.g. colorectal cancer (CRC). Pan-notch inhibitors like gamma-secretase inhibitors (GSIs) have been developed to inhibit Notch and its downstream events. However, severe gastrointestinal toxicity profiles impede the clinical development of GSIs. Provided are novel oligopeptides that specifically inhibit Jag1-Notchl pathway without interfering DLL1 -Notch 1 or DLL4-Notchl, which demonstrate a clear advantage over pan-notch inhibitors. Notch配体(如Jag1)和Notch受体(如Notch1)之间的异常串扰与结肠中的肿瘤发生有关联。因此，抑制Notch通路是治疗具有Jag1上调疾病(如大肠癌(CRC))的吸引方法。为抑制Notch及其下游事件已开发泛Notch抑制剂如γ‑分泌酶抑制剂(GSI)。但是，严重的胃肠道毒性反应阻碍了GSI的临床发展。本发明研发出新颖的寡肽，其可以在不干扰DLL1‑Notch1或DLL4‑Notch1的情况下特异性地抑制Jag1‑Notch1通路，展现出相对于泛Notch抑制剂的明显优势。