DNA-templated spatially controlled proteolysis targeting chimeras for CyclinD1-CDK4/6 complex protein degradation DOI
Rong Zheng, Abhay Prasad, Deeksha Satyabola

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 18, 2024

Abstract Constraining proximity-based drugs, such as proteolysis-targeting chimeras (PROTACs), into its bioactive conformation can significantly impact their selectivity and potency. However, traditional methods for achieving this often involve complex time-consuming synthetic procedures. Here, we introduced an alternative approach by demonstrating DNA-templated spatially controlled PROTACs (DTACs), which leverage the programmability of nucleic-acid based self-assembly efficient synthesis, providing precise control over inhibitors’ spacing orientation. The resulting constructs revealed distance- orientation-dependent degradation potency CyclinD1-CDK4/6 protein in cancer cells. Notably, optimal construct DTAC-V1 demonstrated unprecedented synchronous entire complex. This resulted effective cell cycle arrest G1 phase, further therapeutic studies showed potent anti-tumor effects compared to inhibitors alone. These findings present a novel framework design, offering critical insights that may inform development other proximity-induced modalities.

Language: Английский

ADAR1: from basic mechanisms to inhibitors DOI Creative Commons
Jan Rehwinkel, Parinaz Mehdipour

Trends in Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: July 1, 2024

Adenosine deaminase acting on RNA 1 (ADAR1) converts adenosine to inosine in double-stranded (dsRNA) molecules, a process known as A-to-I editing. ADAR1 deficiency humans and mice results profound inflammatory diseases characterised by the spontaneous induction of innate immunity. In cells lacking ADAR1, unedited RNAs activate sensors. These include melanoma differentiation-associated gene 5 (MDA5) that induces expression cytokines, particularly type I interferons (IFNs), protein kinase R (PKR), oligoadenylate synthase (OAS), Z-DNA/RNA binding (ZBP1). Immunogenic 'defused' may transcripts from repetitive elements other long duplex RNAs. Here, we review these recent fundamental discoveries discuss implications for human diseases. Some tumours depend escape immune surveillance, opening possibility unleashing anticancer therapies with inhibitors.

Language: Английский

Citations

11
A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases DOI Creative Commons
Lin Cheng, Ziying Liu,

Chunxiao Shen

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(1)

Published: Jan. 1, 2025

ABSTRACT Background Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double‐stranded (dsRNA) molecules into inosine a process known as A‐to‐I editing. ADAR1 regulates gene expression output by interacting with and other proteins; plays important roles development, including growth; is linked to innate immunity, tumors, central nervous system (CNS) diseases. Results In recent years, role of tumors has been widely discussed, but its CNS diseases not reviewed. It worth noting that studies have shown great potential treatment neurodegenerative diseases, mechanisms are still unclear. Therefore, it necessary elaborate Conclusions Here, we focus effects such Aicardi–AicardiGoutières syndrome, Alzheimer's disease, Parkinson's glioblastoma, epilepsy, amyotrophic lateral sclerosis, autism. We also evaluate impact ADAR1‐based strategies these particular development new technologies microRNAs, nanotechnology, editing, stem cell therapy. hope provide directions insights for future editing technology brain science

Language: Английский

Citations

1
Z-DNA at the crossroads: untangling its role in genome dynamics DOI

Vinodh J. Sahayasheela,

Mitsuharu Ooga,

Tomotaka Kumagai

et al.

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

1
Proteolysis-targeting drug delivery system (ProDDS): integrating targeted protein degradation concepts into formulation design DOI
Yu Chen, Fengyuan Liu,

Samira Pal

et al.

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(19), P. 9582 - 9608

Published: Jan. 1, 2024

Targeted protein degradation (TPD) has emerged as a revolutionary paradigm in drug discovery and development, offering promising avenue to tackle challenging therapeutic targets. Unlike traditional approaches that focus on inhibiting function, TPD aims eliminate proteins of interest (POIs) using modular chimeric structures. This is achieved through the utilization proteolysis-targeting chimeras (PROTACs), which redirect POIs E3 ubiquitin ligases, rendering them for by cellular ubiquitin-proteasome system (UPS). Additionally, other technologies such lysosome-targeting (LYTACs) autophagy-based degraders facilitate transportation endo-lysosomal or autophagy-lysosomal pathways degradation, respectively. Despite significant growth preclinical research, many fail progress beyond this stage development. Various factors contribute limited success agents, including hurdle inadequate delivery target site. Integrating into platforms could surmount challenges

Language: Английский

Citations

6
PROTAC technology for prostate cancer treatment DOI Creative Commons
Zhen Wang, Dingpeng Zhang, Hiroyuki Inuzuka

et al.

Acta Materia Medica, Journal Year: 2025, Volume and Issue: 4(1)

Published: Jan. 1, 2025

Prostate cancer (PrCa) is the most prevalent urogenital affecting men. PrCa marked by uncontrolled cellular growth that leads to abnormal enlargement of prostate gland. The metastatic spread primary cause mortality, causing cell dissemination distant sites, such as bones, pelvis, and various visceral organs. Key contributors progression include genetic mutations, elevated androgen receptor expression, gene amplification, rise splice variants. Although deprivation therapy remains mainstay for early-stage treatment, efficacy temporary because many cases advance castration-resistant (CRPC), presenting a significant therapeutic hurdle. This review explores key biomarkers latest strategies CRPC with particular focus on innovative proteolysis-targeting chimera (PROTAC) technology. approach offers novel means degrading target proteins we discuss how PROTAC holds potential effective combat resistance mechanisms in CRPC.

Language: Английский

Citations

0
Systematic evolution of functional oligonucleotides for targeted protein degradation DOI

Huang Su,

Yifan Chen, Xuyang Zhao

et al.

Chem, Journal Year: 2025, Volume and Issue: unknown, P. 102408 - 102408

Published: Feb. 1, 2025

Language: Английский

Citations

0
Targeted Degradation of ZBP1 with Covalent PROTACs for Anti‐Inflammatory Treatment of Infections DOI Open Access
Riming Huang,

Yusi Hu,

Yifan Wang

et al.

Angewandte Chemie International Edition, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Z-DNA binding protein 1 (ZBP1) has emerged as a critical pathogen-sensing that upon activation, triggers necroptotic signaling cascades, leading to potent inflammatory response and potentially causing significant tissue damage. However, available drugs specifically developed for the effective inhibition or degradation of ZBP1 is still lacking so far. In this study, we covalent recognition-based PROTAC (C-PROTAC) molecule ZBP1. It consists DNA aptamer recognition moiety an E3 enzyme-recruiting unit, connected by linker containing N-acyl-N-alkyl sulfonamides (NASA) groups. The binds ZBP1, while NASA-containing facilitates formation bond between target protein. ligase-recruiting unit then directs ubiquitin-proteasome system degrade ZBP1-PROTAC complex. This approach combines high specificity aptamers with efficiency degradation-inducing capabilities PROTACs, providing powerful tool targeted degradation. successful application technology highlights its potential selective elimination disease-associated proteins development novel therapeutic strategies.

Language: Английский

Citations

0
Targeted Degradation of ZBP1 with Covalent PROTACs for Anti‐Inflammatory Treatment of Infections DOI Open Access
Riming Huang,

Yusi Hu,

Yifan Wang

et al.

Angewandte Chemie, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Abstract Z‐DNA binding protein 1 (ZBP1) has emerged as a critical pathogen‐sensing that upon activation, triggers necroptotic signaling cascades, leading to potent inflammatory response and potentially causing significant tissue damage. However, available drugs specifically developed for the effective inhibition or degradation of ZBP1 is still lacking so far. In this study, we covalent recognition‐based PROTAC (C‐PROTAC) molecule ZBP1. It consists DNA aptamer recognition moiety an E3 enzyme‐recruiting unit, connected by linker containing N ‐acyl‐ ‐alkyl sulfonamides (NASA) groups. The binds ZBP1, while NASA‐containing facilitates formation bond between target protein. ligase‐recruiting unit then directs ubiquitin‐proteasome system degrade ZBP1‐PROTAC complex. This approach combines high specificity aptamers with efficiency degradation‐inducing capabilities PROTACs, providing powerful tool targeted degradation. successful application technology highlights its potential selective elimination disease‐associated proteins development novel therapeutic strategies.

Language: Английский

Citations

0
USP28-Based Deubiquitinase-Targeting Chimeras for Cancer Treatment DOI
Zhen Wang, C. D. Qian, Yan Xiong

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Deubiquitinase-targeting chimeras (DUBTACs) are an emerging class of therapeutics that can stabilize tumor suppressors by hijacking a deubiquitinase (DUB), thereby offering strategic pivot from conventional approaches to target suppressors. However, only OTUB1 and USP7 have been harnessed for DUBTAC development date. Here, we show the first time USP28 be leveraged developing DUBTACs. Utilizing noncovalent ligand, crafted USP28-recruiting DUBTACs effectively stabilized ΔF508-CFTR mutant protein, with comparable effectiveness previously reported OTUB1- USP7-recruiting CFTR Furthermore, developed cGAS cGAS, elevated cGAS-STING signaling pathway, elicited antiproliferative effect. We also first-in-class PPARγ cancer metabolism pathways. Our lead suppressed cell proliferation, thus providing new potential anticancer therapeutic approach. Hence, this work advances targeted protein stabilization field.

Language: Английский

Citations

0
(GGAA)3-Based TF-PROTACs Enable Targeted Degradation of ETV6 to Inhibit Ewing Sarcoma Growth DOI
Zhichuan Zhu, He Chen, Xing Qiu

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Ewing sarcoma is a rare pediatric cancer primarily driven by the EWS::FLI1 oncofusion transcription factor. Despite being an ideal drug target, has proven challenging to inhibit with conventional approaches. Recent studies identified ETV6 as vulnerability in sarcoma, where it competes at short GGAA repeats restrain function. However, no therapies targeting have been developed. In this study, we report discovery of unique (GGAA)3 DNA oligonucleotide that specifically binds but not EWS::FLI1. We developed (GGAA)3-based TF-PROTACs, termed d(GGAA)3s, coupling VHL ligands. d(GGAA)3s effectively degraded endogenous proteins cells, thus suppressing growth. Mechanistically, enhanced oncogenic transcriptional activity, inducing cellular stress and cell death. Additionally, sensitized cells standard chemotherapy, suggesting their potential use combination therapies. Beyond also targeted ETV6-fusion found breast cancer, broadening clinical applications. summary, represent nucleotide-based approach for degrading ETV6, inhibiting growth ETV6-dependent cancers. This strategy offers promising therapeutic avenue other malignancies involving fusions.

Language: Английский

Citations

0