Mitochondrial Protease Targeting Chimeras for Mitochondrial Matrix Protein Degradation DOI
Dachi Wang, Wenxi Wang, Le Fang

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(23), P. 12861 - 12869

Published: June 5, 2023

Targeted protein degradation (TPD) is an emerging technique for regulation. Currently, all TPD developed in eukaryotic cells relies on either ubiquitin-proteasome or lysosomal systems, thus are powerless against target proteins membrane organelles lacking proteasomes and lysosomes, such as mitochondria. Here, we a mitochondrial protease targeting chimera (MtPTAC) to address this issue. MtPTAC bifunctional small molecule that can bind caseinolytic P (ClpP) at one end the other. Mechanistically, activates hydrolase activity of ClpP while simultaneously bringing into proximity with ClpP. Taking RNA polymerase (POLRMT) model protein, have demonstrated powerful proteolytic ability antitumor application prospects MtPTAC, both vivo vitro. This first modularly designed specifically hydrolyze inside

Language: Английский

Acetylation Targeting Chimera Enables Acetylation of the Tumor Suppressor p53 DOI
Md Kabir, Ning Sun, Xiao Hu

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(27), P. 14932 - 14944

Published: June 26, 2023

With advances in chemically induced proximity technologies, heterobifunctional modalities such as proteolysis targeting chimeras (PROTACs) have been successfully advanced to clinics for treating cancer. However, pharmacologic activation of tumor-suppressor proteins cancer treatment remains a major challenge. Here, we present novel Acetylation Targeting Chimera (AceTAC) strategy acetylate the p53 tumor suppressor protein. We discovered and characterized first p53Y220C AceTAC, MS78, which recruits histone acetyltransferase p300/CBP mutant. MS78 effectively acetylated lysine 382 (K382) concentration-, time-, p300-dependent manner suppressed proliferation clonogenicity cells harboring mutation with little toxicity wild-type p53. RNA-seq studies revealed p53Y220C-dependent upregulation TRAIL apoptotic genes downregulation DNA damage response pathways upon acetylation by MS78. Altogether, AceTAC could provide generalizable platform proteins, suppressors, via acetylation.

Language: Английский

Citations

28
PROTACs: A novel strategy for cancer drug discovery and development DOI Creative Commons
Xin Han, Yi Sun

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 29, 2023

Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: small molecule that binds to target protein, an E3 ligase ligand (consisting and its recruiter), chemical linker hooks first two components together. In the past 20 years, we have witnessed advancement multiple degraders into clinical trials anticancer therapies. However, one major challenges is only very limited number recruiters are currently available as targeted protein degradation (TPD), although human genome encodes more than 600 ligases. Thus, there urgent need identify additional effective TPD applications. this review, summarized existing RING-type ubiquitin their act ligands application discovery. We believe review could serve reference future development efficient cancer discovery development.

Language: Английский

Citations

25
Ubiquitin-specific proximity labeling for the identification of E3 ligase substrates DOI
Hai‐Tsang Huang, Ryan J. Lumpkin,

Ryan W. Tsai

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(9), P. 1227 - 1236

Published: March 21, 2024

Language: Английский

Citations

16
Antitumor Effect of Anti‐c‐Myc Aptamer‐Based PROTAC for Degradation of the c‐Myc Protein DOI Creative Commons
Yuchun Wang, Gang Yang, Xinyu Zhang

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(26)

Published: April 29, 2024

Abstract Targeting “undruggable” targets with intrinsically disordered structures is of great significance for the treatment disease. The transcription factor c‐Myc controls global gene expression and an attractive therapeutic target multiple types cancers. However, due to lack defined ligand binding pockets, targeted have thus far been unsuccessful. Herein, address dilemma lacking ligands, efficient high throughput aptamer screening strategy established, named polystyrene microwell plate‐based systematic evolution ligands by exponential enrichment (microwell‐SELEX), identify specific (MA9C1) against c‐Myc. multifunctional aptamer‐based Proteolysis Chimeras (PROTAC) proteolysis (ProMyc) developed using MA9C1 as ligand. ProMyc not only significantly degrades ubiquitin‐proteasome system, but also reduces Max protein, synergistically inhibiting transcriptional activity. Combination artificial cyclization anti‐PD‐L1 (PA1)‐based delivery circular PA1‐ProMyc chimeras achieve tumor regression in xenograft model, laying a solid foundation development efficacious degrader clinic. Therefore, this provides invaluable potential drug discovery anti‐tumor therapy, offering promising overcome challenge targeting intractable targets.

Language: Английский

Citations

11
Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety DOI
Renshuai Zhang, Songbo Xie, Jie Ran

et al.

Journal of Cellular Physiology, Journal Year: 2024, Volume and Issue: 239(5)

Published: March 19, 2024

Abstract Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in therapeutic drug development by leveraging the ubiquitin‐proteasome system to enable targeted protein degradation, particularly impacting oncology. This review delves into various types of PROTACs, such as peptide‐based, nucleic acid‐based, and small molecule each addressing distinct challenges degradation. It also discusses innovative strategies like bridged PROTACs conditional switch‐activated offering precise targeting previously “undruggable” proteins. The potential extends beyond oncology, with ongoing research technological advancements needed maximize their potential. Future progress this field relies on interdisciplinary collaboration integration advanced computational tools open new treatment avenues across diseases.

Language: Английский

Citations

10
The emerging role of E3 ubiquitin ligases and deubiquitinases in metabolic dysfunction-associated steatotic liver disease DOI Creative Commons
Yu Zhang, Jiahui Yang, Jiali Min

et al.

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 25, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic worldwide, with a prevalence as high 32.4%. MASLD encompasses spectrum of pathologies, ranging from steatosis to metabolic steatohepatitis (MASH), fibrosis, and, in some cases, progression end-stage (cirrhosis and hepatocellular carcinoma). A comprehensive understanding pathogenesis this highly prevalent may facilitate identification novel targets for development improved therapies. E3 ubiquitin ligases deubiquitinases (DUBs) are key regulatory components ubiquitin‒proteasome system (UPS), which plays pivotal role maintaining intracellular protein homeostasis. Emerging evidence implicates that aberrant expression DUBs involved MASLD. Here, we review abnormalities by (1) discussing their targets, mechanisms, functions MASLD; (2) summarizing pharmacological interventions targeting these enzymes preclinical clinical studies; (3) addressing challenges future therapeutic strategies. This synthesizes current highlight strategies based on UPS progressive disease.

Language: Английский

Citations

1
Development of PROTAC degrader probe of CDK4/6 based on DCAF16 DOI
Chunlan Pu, Yuanyuan Liu, Rui Deng

et al.

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 138, P. 106637 - 106637

Published: May 26, 2023

Language: Английский

Citations

18
Dual‐Programmable Semiconducting Polymer NanoPROTACs for Deep‐Tissue Sonodynamic‐Ferroptosis Activatable Immunotherapy DOI

Fengshuo Wang,

Guoqiang Dong,

Mengbin Ding

et al.

Small, Journal Year: 2023, Volume and Issue: 20(8)

Published: Oct. 10, 2023

Abstract Proteolysis‐targeting chimeras (PROTACs) can provide promising opportunities for cancer treatment, while precise regulation of their activities remains challenging to achieve effective and safe therapeutic outcomes. A semiconducting polymer nanoPROTAC (SPN FeP ) is reported that ultrasound (US) tumor microenvironment dual‐programmable PROTAC activity deep‐tissue sonodynamic‐ferroptosis activatable immunotherapy. SPN formed through a nano‐precipitation sonodynamic polymer, ferroptosis inducer, newly synthesized molecule. The polymers work as sonosensitizers produce singlet oxygen ( 1 O 2 via effect under US irradiation, inducers react with intratumoral hydrogen peroxide (H generate hydroxyl radical (·OH). Such reactive species (ROS) generation not only triggers immunogenic cell death (ICD), but also induces on‐demand delivery molecules into sites. effectively activated nanoPROTACs degrade nicotinamide phosphoribosyl transferase (NAMPT) suppress infiltration myeloid‐derived suppressive cells (MDSCs), thus promoting antitumor immunity. In such way, mediates immunotherapy entirely inhibiting growths in both subcutaneous 2‐cm tissue‐covered deep mouse models. This study presents strategy based on PROTACs combinational therapy.

Language: Английский

Citations

18
Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex DOI
Mingyu Wang, Rongkun Lin, Jiacheng Li

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(7), P. 4932 - 4951

Published: March 17, 2023

The CDK8–cyclin C complex is an important anti-tumor target, but unlike CDK8, cyclin remains undruggable. Modulators regulating activity directly are still under development. Here, a series of hydrophobic tagging-based degraders the were designed, synthesized, and evaluated to identify first dual degrader, LL-K8-22, which induced selective synchronous degradation CDK8 C. Proteomic immunoblot studies exhibited that LL-K8-22 significantly degraded without reducing CDK19 did not degrade other proteins except Moreover, showed enhanced anti-proliferative effects over its parental molecule, BI-1347, with potency increased by 5-fold in MDA-MB-468 cells. more pronounced on downstream signaling than suppressing STAT1 phosphorylation persistently. RNA-sequencing analysis revealed inhibited E2F- MYC-driven carcinogenic transcriptional programs. Overall, first-in-class degrader would be useful for studying unknown functions

Language: Английский

Citations

17
Targeting autophagy drug discovery: Targets, indications and development trends DOI

Mengjia Jiang,

Wayne Wu,

Zijie Xiong

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 267, P. 116117 - 116117

Published: Jan. 23, 2024

Language: Английский

Citations

7