In Vivo Self‐Assembly of PROTACs by Bioorthogonal Chemistry for Precision Cancer Therapy DOI
Shaowen Xie, Jingjie Zhu, Yihan Peng

и другие.

Angewandte Chemie, Год журнала: 2024, Номер unknown

Опубликована: Дек. 23, 2024

Abstract Proteolysis targeting chimeras (PROTACs) hold immense promise for targeted protein degradation; however, challenges such as off‐target effects, poor drug‐likeness properties, and the “hook effect” remain. This study introduces Nano‐Click‐formed PROTACs (Nano‐CLIPTACs) precise tumor degradation in vivo. Traditional with high molecular weight were first divided into two smaller druglike precursors capable of self‐assembling to form functional through a bioorthogonal reaction. Then, optimal CLIPTACs ( W4 Z2 ) encapsulated individually cyclic RGDfC‐peptide‐modified liposomes prepare Nano‐CLIPTACs, enabling tumor‐targeted delivery subsequent situ self‐assembly WZ42 within cells. The abilities Nano‐CLIPTACs vitro vivo further verified using key oncology target, anaplastic lymphoma kinase (ALK), validating safety, efficacy “anti‐hook this strategy. Overall, represent critical step towards clinical translation technology anti‐cancer therapies.

Язык: Английский

Accelerating PROTACs Discovery Through a Direct‐to‐Biology Platform Enabled by Modular Photoclick Chemistry DOI Creative Commons

Ke‐Nian Yan,

Yong‐Qiang Nie,

Jiayu Wang

и другие.

Advanced Science, Год журнала: 2024, Номер 11(26)

Опубликована: Апрель 30, 2024

Abstract Proteolysis targeting chimeras (PROTACs) have emerged as a promising strategy for drug discovery and exploring protein functions, offering revolutionary therapeutic modality. Currently, the predominant approach to PROTACs mainly relies on an empirical design–synthesis–evaluation process involving numerous cycles of labor‐intensive synthesis‐purification bioassay data collection. Therefore, development innovative methods expedite PROTAC synthesis exploration chemical space remains highly desired. Here, direct‐to‐biology is reported streamline libraries plates, enabling seamless transfer reaction products cell‐based bioassays without need additional purification. By integrating amide coupling light‐induced primary amines o‐nitrobenzyl alcohols cyclization (PANAC) photoclick chemistry into plate‐based synthetic process, this produces with high efficiency structural diversity. Moreover, by employing platform screening, we smoothly found potent effectively inhibit triple‐negative breast cancer (TNBC) cell growth induce rapid, selective targeted degradation cyclin‐dependent kinase 9 (CDK9). The study introduces versatile assembling followed direct biological evaluation. This provides opportunity high‐throughput libraries, thereby enhancing accelerating PROTACs.

Язык: Английский

Процитировано

7
Triazination/IEDDA Cascade Modular Strategy Installing Pyridines/Pyrimidines onto Tyrosine Enables Peptide Screening and Optimization DOI
Quan Zuo,

Xinyi Song,

Jie Yan

и другие.

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Modular chemical postmodification of peptides is a promising strategy that supports the optimization and innovation hit peptide therapeutics by enabling rapid derivatization. However, current methods are primarily limited to traditional bio-orthogonal strategies ligation techniques, which require preintroduction non-natural amino acids impose fixed limit diversity. Here, we developed Tyrosine-1,2,3-Triazine Ligation (YTL) strategy, constructs novel linkages (pyridine pyrimidine) through "one-pot, two-step" process combining SNAr IEDDA reactions, promoting modular post modification Tyr-containing peptides. After optimizing YTL establishing standard procedures, successfully applied it solid-phase various biorelated peptides, such as synthesis dual-mode imaging probes long-acting GLP-1 analogs. As proof concept, library 384 amphipathic was constructed using based on 96-well microfiltration plates. modifications were then performed screened template tripeptide RYR, leading generation 20 derivatives. The antibacterial activity these derivatives systematically characterized, identifying Z8 potential candidate.

Язык: Английский

Процитировано

0
Workflow for E3 Ligase Ligand Validation for PROTAC Development DOI Creative Commons

Nebojša Miletić,

Janik Weckesser, Thorsten Mosler

и другие.

ACS Chemical Biology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 11, 2025

Proteolysis targeting chimeras (PROTACs) have gained considerable attention as a new modality in drug discovery. The development of PROTACs has been mainly focused on using CRBN (Cereblon) and VHL (Von Hippel-Lindau ligase) E3 ligase ligands. However, the size human family, newly developed ligands, favorable druggability some families hold promise that novel degraders with unique pharmacological properties will be designed future this large space. Here, we workflow aiming to improve streamline evaluation ligand efficiency for PROTAC assessment corresponding "degradable" target space broad-spectrum kinase inhibitors well-established VH032 validation system. Our study revealed linker attachment points are highly efficient degradation well pitfalls when protein readout. For instance, cytotoxicity was identified major mechanism leading PROTAC- VHL-independent degradation. combination negative controls, competition by parent compounds, neddylation proteasome essential distinguish between VHL-dependent -independent events. We share here findings limitations our hope provide guidance evaluations systems degrader development.

Язык: Английский

Процитировано

0
General Platform for Efficient and Modular Assembly of GalNAc–siRNA Conjugates via Primary Amines and o-Nitrobenzyl Alcohol Cyclization Photoclick Chemistry Enabling Rapid Access to Therapeutic Oligonucleotides DOI Creative Commons

Hui-Jun Nie,

Hao Hu, Xinming Qi

и другие.

JACS Au, Год журнала: 2025, Номер 5(3), С. 1402 - 1412

Опубликована: Фев. 24, 2025

Oligonucleotide-based therapies, especially ligand-conjugated siRNAs, offer significant therapeutic potential for a wide array of diseases. However, conventional solid-phase synthesis and current postsynthetic in-solution conjugation methods face notable challenges related to efficiency, accessibility, the scalability diverse ligand–oligonucleotide conjugates. Herein, we introduce novel strategy highly efficient, rapid, modular assembly GalNAc–siRNA conjugates based on light-induced primary amine o-nitrobenzyl alcohol cyclization (PANAC) chemistry. Leveraging advantages PANAC photoclick chemistry linkers, our method enables direct trivalent GalNAc (tGalNAc) with commercially available primary-amine-modified siRNAs. This approach demonstrates efficient rapid therapeutically relevant oligonucleotides ligands interest, offering operational simplicity practicality; thus, it effectively overcomes limitations existing methods. More importantly, developed siRNA–tGalNAc showed robust gene silencing effect superior parent siRNA conjugate, highlighting effectiveness in generating screening enhance vivo potency. Overall, oligonucleotide–tGalNAc using readily accessible tGalNAc-amine ligands. expands toolkit conjugates, providing general platform broad applicability, thereby advancing optimization development oligonucleotide-based therapeutics.

Язык: Английский

Процитировано

0
Harnessing the Power of Natural Products for Targeted Protein Degradation DOI

Bo Zhu,

Zheng Wu,

Yiwen Shou

и другие.

Medicinal Research Reviews, Год журнала: 2025, Номер unknown

Опубликована: Апрель 30, 2025

ABSTRACT Natural products have garnered significant attention due to their complex chemical structures and remarkable pharmacological activities. With inherent recognition capabilities for protein surfaces, natural serve as ideal candidates designing proteolysis‐targeting chimeras (PROTACs). The utilization of in PROTAC development offers distinct advantages, including rich diversity, multitarget activities, sustainable sourcing. This comprehensive review explores the vast potential harnessing research. Moreover, discusses application degradant technology, which involves utilizing product‐based compounds selectively degrade disease‐causing proteins, well implementation computer‐aided drug design (CADD) technology identifying suitable targets degradation within realm products. By power leveraging computational tools, PROTACs derived from revolutionize discovery provide innovative therapeutic interventions various diseases.

Язык: Английский

Процитировано

0
Drug discovery technologies–Current and future trends DOI

Mark C. Noe,

Claire M. Steppan,

Andrea D. Weston

и другие.

Elsevier eBooks, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Fluorescence-Coupled Ubiquitination Assay as a High-Throughput Screening Strategy for Novel Cereblon Degraders DOI
Yanan Deng,

Shiling Yang,

Hesong Xu

и другие.

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Май 7, 2025

Cereblon (CRBN)-based protein degradation, via molecular glue degraders (MGDs) and proteolysis-targeting chimeras (PROTACs), is a promising cancer treatment strategy in targeted degradation (TPD). However, novel discovery remains limited due to the lack of robust, high-throughput screening (HTS) methods for processing pools purified compounds or complex chemical synthesis mixtures. Here, we introduce an innovative HTS that employs highly sensitive, fluorescence-coupled ubiquitination assay identify CRBN-based degraders. This approach tracks ubiquitinated target proteins gel-based analyses, thereby progressively narrows down list potential degrader molecules from large-scale compound libraries reaction Using this strategy, identified LL-BPTF-8, lead PROTAC with high potency selectivity targets bromodomain PHD finger transcription factor (BPTF). Overall, our method offers low-cost, rapid, versatile platform candidates, significantly streamlining

Язык: Английский

Процитировано

0
To homeostasis and beyond! Recent advances in the medicinal chemistry of heterobifunctional derivatives DOI

Diana Castagna,

Benoit Gourdet,

Roland Hjerpe

и другие.

Progress in medicinal chemistry, Год журнала: 2024, Номер unknown, С. 61 - 160

Опубликована: Янв. 1, 2024

Язык: Английский

Процитировано

1
In Vivo Self‐Assembly of PROTACs by Bioorthogonal Chemistry for Precision Cancer Therapy DOI
Shaowen Xie, Jingjie Zhu, Yihan Peng

и другие.

Angewandte Chemie International Edition, Год журнала: 2024, Номер unknown

Опубликована: Дек. 23, 2024

Abstract Proteolysis targeting chimeras (PROTACs) hold immense promise for targeted protein degradation; however, challenges such as off‐target effects, poor drug‐likeness properties, and the “hook effect” remain. This study introduces Nano‐Click‐formed PROTACs (Nano‐CLIPTACs) precise tumor degradation in vivo. Traditional with high molecular weight were first divided into two smaller druglike precursors capable of self‐assembling to form functional through a bioorthogonal reaction. Then, optimal CLIPTACs ( W4 Z2 ) encapsulated individually cyclic RGDfC‐peptide‐modified liposomes prepare Nano‐CLIPTACs, enabling tumor‐targeted delivery subsequent situ self‐assembly WZ42 within cells. The abilities Nano‐CLIPTACs vitro vivo further verified using key oncology target, anaplastic lymphoma kinase (ALK), validating safety, efficacy “anti‐hook this strategy. Overall, represent critical step towards clinical translation technology anti‐cancer therapies.

Язык: Английский

Процитировано

1
In Vivo Self‐Assembly of PROTACs by Bioorthogonal Chemistry for Precision Cancer Therapy DOI
Shaowen Xie, Jingjie Zhu, Yihan Peng

и другие.

Angewandte Chemie, Год журнала: 2024, Номер unknown

Опубликована: Дек. 23, 2024

Abstract Proteolysis targeting chimeras (PROTACs) hold immense promise for targeted protein degradation; however, challenges such as off‐target effects, poor drug‐likeness properties, and the “hook effect” remain. This study introduces Nano‐Click‐formed PROTACs (Nano‐CLIPTACs) precise tumor degradation in vivo. Traditional with high molecular weight were first divided into two smaller druglike precursors capable of self‐assembling to form functional through a bioorthogonal reaction. Then, optimal CLIPTACs ( W4 Z2 ) encapsulated individually cyclic RGDfC‐peptide‐modified liposomes prepare Nano‐CLIPTACs, enabling tumor‐targeted delivery subsequent situ self‐assembly WZ42 within cells. The abilities Nano‐CLIPTACs vitro vivo further verified using key oncology target, anaplastic lymphoma kinase (ALK), validating safety, efficacy “anti‐hook this strategy. Overall, represent critical step towards clinical translation technology anti‐cancer therapies.

Язык: Английский

Процитировано

0