Tumor hypoxia-activated proteolysis targeting chimeras (ha-PROTACs) 9 and 10 were designed and synthesized by incorporating the hypoxia-activated leaving group (1-methyl-2-nitro-1H-imidazol-5-yl)methyl or 4‑nitrobenzyl into the structure of the cereblon (CRBN) E3 ligand of an epidermal growth factor receptor 19 deletions (EGFR Del19 -based PROTAC 8 . The in vitro protein degradation assay demonstrated that 9 and 10 could effectively and selectively degrade EGFR Del19 in tumor hypoxia. Meanwhile, these two compounds showed higher potency in inhibiting cell viability and migration, as well as in promoting cells apoptosis in tumor hypoxia. Moreover, nitroreductase reductive activation assay indicated that prodrugs 9 and 10 could successfully release the active compound 8 . This study confirmed the feasibility to develop ha-PROTACs to enhance the selectivity of PROTACs by caging CRBN E3 ligase ligand.
Proteolysis-targeting chimera (PROTAC) that specifically targets harmful proteins for destruction by hijacking the ubiquitin-proteasome system (UPS) is emerging as a potent anti-cancer strategy. How to efficiently modulate the target degradation remains a challenging issue. In this study, we employ a single amino acid-based PROTAC, which uses the shortest degradation signal sequence as the ligand of the N-end rule E3 ubiquitin ligases to degrade the fusion protein BCR-ABL, an oncogenic kinase that drives the progression of chronic myeloid leukemia (CML). We find that the reduction level of BCR-ABL can be easily adjusted by substituting different amino acids. Furthermore, a single PEG linker is found to achieve the best proteolytic effect. Our efforts have resulted in effective degradation of BCR-ABL protein by the N-end rule pathway and efficient growth inhibition of K562 cells expressing BCR-ABL in vitro , and blunted tumor growth in a K562 xenograft tumor model in vivo . The PROTAC presented has unique advantages including lower effective concentration, smaller molecular size and modular degradation rate. Demonstrating the efficacy of the N-end rule-based PROTACs in vitro and in vivo , our study further expands the limited degradation pathways currently available for PROTACs in vivo and is easily adapted for broader applications in targeted protein degradation.
Proteolysis targeting chimeras (PROTACs) have been utilized to overcome drug resistance by degrading mutant EGFR in non-small cell lung cancer (NSCLC) therapy. However, their therapeutic efficacy is often compromised by the complex tumor microenvironment, which can lead to the reduced sensitivity of lung cancer cells to PROTACs. In this study, oxygen supplier (CaO 2 ) and PROTAC co-loaded liposomes (LCP) are developed for simultaneously promoting EGFR degradation and hypoxic microenvironment alleviation. Calcium peroxide (CaO 2 ) can release oxygen to modulate the hypoxic microenvironment, thereby reducing HIF-1α expression and enhancing the sensitivity of lung cancer cells. Compared with PROTACs administered alone, LCP exhibited enhanced tumor cell killing effect, improved protein degradation capacity, and superior tumor growth inhibition in NSCLC animal models. Mechanistic analysis reveals that LCP modulates hypoxia-associated proteins, including FGFR1, ERK, and TGF-α, contributing to the enhanced therapeutic efficacy. The LCP developed herein offers a strategy for enhancing NSCLC therapy by remodeling the hypoxic tumor microenvironment.
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