dBET57(Dana-Farber Cancer Institute)

Protein degraders, such as bifunctional proteolysis-targeting chimeras (PROTACs), selectively eliminate target proteins by leveraging the natural protein degradation machinery. PROTACs bridge the target protein with an E3 ligase, which induces ubiquitination and degradation. Investigating ternary complex structures elucidates the molecular mechanisms of their formation and degradation. This study examines the binding dynamics of E3 ligases (VHL, CRBN, and cIAP) with proteins of interest, focusing on dynamics, cooperativity, selectivity, linker length, and PROTAC conformations. The influence of interface residues and linker lengths on specific conformations for target proteins and E3 ligases is highlighted. Utilizing molecular dynamics and steered molecular dynamics simulations, the study provides comprehensive parameters on the behavior and stability of diverse ternary complexes. These insights are crucial for designing PROTACs targeting disease-causing proteins and advancing the development of degradable ternary complexes for therapeutic applications.

The chemo‐regulation abilities of chemotherapeutic medications are appealing to address the low immunogenicity, immunosuppressive lactate microenvironment, and adaptive immune resistance of colorectal cancer. In this work, the proteolysis targeting chimera (PROTAC) of BRD4 (dBET57) is found to downregulate colorectal cancer glycolysis through the transcription inhibition of c‐Myc, which also inhibits the expression of programmed death ligand 1 (PD‐L1) to reverse immune evasion and avoid adaptive immune resistance. Based on this, self‐delivery nano‐PROTACs (designated as DdLD NPs) are further fabricated by the self‐assembly of doxorubicin (DOX) and dBET57 with the assistance of DSPE‐PEG2000. DdLD NPs can improve the stability, intracellular delivery, and tumor targeting accumulation of DOX and dBET57. Meanwhile, the chemotherapeutic effect of DdLD NPs can efficiently destroy colorectal cancer cells to trigger a robust immunogenic cell death (ICD). More importantly, the chemo‐regulation effects of DdLD NPs can inhibit colorectal cancer glycolysis to reduce the lactate production, and downregulate the PD‐L1 expression through BRD4 degradation. Taking advantages of the chemotherapy and chemo‐regulation ability, DdLD NPs systemically activated the antitumor immunity to suppress the primary and metastatic colorectal cancer progression without inducing any systemic side effects. Such self‐delivery nano‐PROTACs may provide a new insight for chemotherapy‐enabled tumor immunotherapy.