Expanding the horizons of targeted protein degradation: A non-small molecule perspective

Huang, Xiaowei; Wu, Fengbo; Ye, Jing; Wang, Lian; Wang, Xiaoyun; Li, Xiang; He, Gu

doi:10.1016/j.apsb.2024.01.010

Cited by 5 publications

(3 citation statements)

References 222 publications

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“…In recent years, non-small-molecule degraders have received considerable attention (42). Here, we investigated the role of the palmitoyltransferase DHHC3 in inhibiting PD-L1 expression using the TPD method.…”

Section: Introductionmentioning

confidence: 99%

Treating ICB-Resistant Cancer by Inhibiting PD-L1 via DHHC3 Degradation Induced by Cell Penetrating Peptide-Induced Chimera Conjugates

Liu,

Shi,

Tan

et al. 2024

Preprint

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The current selection of ligands for both proteins of interest (POI) and E3 ubiquitin ligase significantly restricts the scope of targeted protein degradation (TPD) technologies. This study introduces cell-penetrating peptide-induced chimera conjugates (cp-PCCs) targeting the DHHC3 enzyme involved in PD-L1 palmitoylation. This approach disrupts PD-L1's immunosuppressive function, enhancing anti-tumor immunity. We developed cp-PCCs to degrade DHHC3, directly linking DHHC3-mediated PD-L1 palmitoylation to PD-L1 stability on tumor cells. Our research utilized both in vitro assays and in vivo experiments in immune checkpoint blockade-resistant mouse models. We focused on a CRBN-based cp-PCC named PCC16, which demonstrated a DC50 of 102 nmol for DHHC3 degradation and significantly reduced PD-L1 levels. In resistant models, PCC16 not only robustly downregulated PD-L1 but also exhibited substantial anti-tumor activity in vivo without significant toxicity. This outperformed traditional inhibitors, showcasing the potential of cp-PCC technology to bypass current PROTAC limitations. Our findings suggest that cp-PCCs offer a promising method for targeting PD-L1 through DHHC3 inhibition and support their continued exploration as a versatile tool in cancer immunotherapy, especially for tumors resistant to standard treatments.

show abstract

Section: Introductionmentioning

confidence: 99%

Treating ICB-Resistant Cancer by Inhibiting PD-L1 via DHHC3 Degradation Induced by Cell Penetrating Peptide-Induced Chimera Conjugates

Liu,

Shi,

Tan

et al. 2024

Preprint

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“…The ligand design, achieving tissue specificity, and addressing potential off-target effects present formidable obstacles. 8,9 To optimize the clinical utility of PROTACs, researchers delve into understanding their kinetics with a specific focus on affinity and cooperativity. These parameters play prominent roles in the dynamic process of the PROTAC ternary complex formation and stability by influencing the temporal aspects of action.…”

mentioning

confidence: 99%

“…PROTACs have revolutionized drug development with advantages like target flexibility, high potency, exceptional selectivity, sustained depletion, overcoming resistance, modularity, targeting of “undruggable” proteins, catalytic activity, and efficient operation with low-affinity ligands. The ligand design, achieving tissue specificity, and addressing potential off-target effects present formidable obstacles. , To optimize the clinical utility of PROTACs, researchers delve into understanding their kinetics with a specific focus on affinity and cooperativity. These parameters play prominent roles in the dynamic process of the PROTAC ternary complex formation and stability by influencing the temporal aspects of action.…”

mentioning

confidence: 99%

Interplay of PROTAC Complex Dynamics for Undruggable Targets: Insights into Ternary Complex Behavior and Linker Design

Kumar,

Sobhia

2024

ACS Med. Chem. Lett.

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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.

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Comprehensive approaches to preclinical evaluation of monoclonal antibodies and their next-generation derivatives

Singh,

Kachhawaha,

Singh

2024

Biochemical Pharmacology

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Expanding the horizons of targeted protein degradation: A non-small molecule perspective

Cited by 5 publications

References 222 publications

Treating ICB-Resistant Cancer by Inhibiting PD-L1 via DHHC3 Degradation Induced by Cell Penetrating Peptide-Induced Chimera Conjugates

Treating ICB-Resistant Cancer by Inhibiting PD-L1 via DHHC3 Degradation Induced by Cell Penetrating Peptide-Induced Chimera Conjugates

Interplay of PROTAC Complex Dynamics for Undruggable Targets: Insights into Ternary Complex Behavior and Linker Design

Comprehensive approaches to preclinical evaluation of monoclonal antibodies and their next-generation derivatives

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