Discovery of Stapled Peptide MYC Degrader with Potent In Vivo Activities for Triple-Negative Breast Cancer Therapy.

Harnessing the E3 Ligase KLHL12 for Tumor-Selective Protein Degradation.

KLHL12 is identified as a potentially tumor-selective E3 ligase and the development of the first-in-class KLHL12-recruiting PROTACs are reported, which established KLHL12 as a promising tumor‑selective E3 ligase and provided a KLHL12-recruiting PROTAC platform for cancer therapy.

Discovery of rigid linker-based CDK4/6 PROTACs for the treatment of breast cancer.

Selective cyclin-dependent kinase (CDK) 4/6 inhibitors play a leading role in the treatment of breast cancer; however, their efficacy is often limited by acquired resistance. Proteolysis-targeting chimera (PROTAC) technology has recently emerged as a promising therapeutic strategy to overcome drug resistance. In this study, we designed and synthesized a series of novel CDK4/6 PROTACs based on dalpiciclib incorporating rigid linkers. The optimal compound P11 exhibited potent and selective CDK4/6 degradation activity mediated by the ubiquitin-proteasome system. Binding model analysis demonstrated that P11 is capable of forming a stable CDK6-CRBN-P11 ternary complex. P11 significantly inhibited proliferation and colony formation, and induced cell cycle arrest in breast cancer cell lines. Furthermore, P11 effectively suppressed tumor growth in an MCF-7 xenograft model, demonstrating stronger anti-breast cancer activity than dalpiciclib both in vitro and in vivo. Importantly, P11 showed potential to overcome acquired resistance to CDK4/6 inhibitors. Therefore, P11 could be a promising preclinical candidate for further development.

Novel VHL ligand-based PROTACs targeting JNK1: design, synthesis, and biological evaluation with potent anti-EMT activity.

This work describes the design, synthesis, and biological evaluation of a series of JNK1-targeting PROTACs that recruit either CRBN or VHL E3 ligases that demonstrates excellent degradation potency and selectivity for JNK1, highlighting its potential as a valuable chemical probe for EMT-associated pathologies.

Design, synthesis, and biological characterization of a hydrophobic tagging EGFR degrader for the treatment of non-small-cell lung cancer.

Structure-Guided Optimization of p62-Directed AUTOTACs for Efficient EGFR/VEGFR2 Degradation and Antitumor Efficacy.

Receptor tyrosine kinases (RTKs) are core cancer therapeutic targets, yet their integral membrane localization hinders efficient degradation by traditional ubiquitin-proteasome system (UPS)-based targeted protein degradation (TPD) strategies. Herein, we describe the structure-guided development of p62/SQSTM1-directed autophagy-targeting chimera (AUTOTAC) degraders targeting RTKs. Medicinal chemistry optimization yielded two potent AUTOTACs, 6d and 11bg, which selectively degrade EGFR and VEGFR2, respectively. Mechanistic studies confirmed that these degraders act via p62 recruitment and autophagy-lysosome pathway activation in a UPS-independent manner. 6d and 11bg exhibited robust antiproliferative, proapoptotic, and antimigratory effects in vitro, and 6d further demonstrated significant in vivo antitumor efficacy with good tolerability in xenograft models. This study validates AUTOTAC technology for RTK degradation, offering a new approach to address TKI resistance and broaden the TPD landscape.

Combinatorial screening of biological degrader modules identifies heterobifunctional molecules that efficiently destroy MYC, leading to rapid tumour cell death in vitro and in vivo

Targeted protein degradation is a potent strategy against intracellular proteins impervious to traditional drugs. We describe a platform reliant on high-throughput cloning and mRNA-based delivery to quickly screen 100s-1000s of modular biological degraders, which we challenge against the high-turnover c-Myc oncoprotein. We uncover critical principles to drive degrader discovery against any target, free from tagging or prior cell line engineering, with direct applications in research and potentially therapy. We demonstrate the feasibility of targeted protein degradation of c-Myc across in vitro cancer models and in vivo xenograft model, uncovering distinct cellular responses between c-Myc degradation and inhibition.