MYC-Targeting Inhibitors Generated from a Stereodiversified Bicyclic Peptide Library

作者：Z. Li, Yi Huang, Ta I Hung, Jianan Sun, Desiree Aispuro, Boxi Chen, Nathan Guevara, Fei Ji, Cong Xu, Lingchao Zhu, Siwen Wang, Zhili Guo, Chia‐en A. Chang, Min Xue · 发表于：Journal of the American Chemical Society · 年份：2024 · DOI：10.1021/jacs.3c09615 · 被引用次数：25 · 研究领域：Protein Degradation and Inhibitors、Chemical Synthesis and Analysis、Cancer-related gene regulation

High Resolution Image Download MS PowerPoint Slide Here, we present the second generation of our bicyclic peptide library (NTB), featuring a stereodiversified structure and a simplified construction strategy. We utilized a tandem ring-opening metathesis and ring-closing metathesis reaction (ROM-RCM) to cyclize the linear peptide library in a single step, representing the first reported instance of this reaction being applied to the preparation of macrocyclic peptides. Moreover, the resulting bicyclic peptide can be easily linearized for MS/MS sequencing with a one-step deallylation process. We employed this library to screen against the E 363 -R 378 epitope of MYC and identified several MYC-targeting bicyclic peptides. Subsequent in vitro cell studies demonstrated that one candidate, NT-B2R, effectively suppressed MYC transcription activities and cell proliferation.