MYC-Targeting PROTACs Lead to Bimodal Degradation and N-Terminal Truncation DOI
Shelton R. Boyd, Srinivas Chamakuri, Alexander J. Trostle

et al.

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 27, 2025

MYC is a master regulatory transcription factor whose sustained dysregulation promotes the initiation and maintenance of numerous cancers. While regarded as potenial therapeutic target in cancer, its intrinsically disordered structure has proven to be formidable barrier toward development highly effective small molecule inhibitors. We rationalized that proteolysis targeting chimeras (PROTACs), which might accomplish targeted degradation MYC, would achieve more potent cell killing MYC-driven cancer cells than reversible PROTACs are bifunctional molecules designed produce ternary complex between protein an E3 ligase leading target's ubiquitination by 26S proteasome. generated PROTAC MTP3 based on modifications previously reported MYC-targeting compound KJ-Pyr-9. found depletes endogenous full-length proteins uniquely induces increasing levels functional, N-terminally truncated species, tMYC. Furthermore, perturbs cellular favor tMYC-dominated state gene landscape not significantly altered compared wild type MYC. Moreover, although it lacks ∼10 kDa MYC's N-terminal transactivation domain, tMYC sufficient maintain oncogenic proliferative state. Our results highlight complexities proximity-inducing compounds against regulated conformationally dynamic targets such indicate can induce alternative outcomes beyond degradation.

Language: Английский

An overview of PROTACs: a promising drug discovery paradigm DOI Creative Commons

Liu Zi,

Mingxing Hu,

Yang Yu

et al.

Molecular Biomedicine, Journal Year: 2022, Volume and Issue: 3(1)

Published: Dec. 20, 2022

Abstract Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin–proteasome system. Currently, about 20–25% of all protein targets being studied, and most works focus on their enzymatic functions. Unlike small molecules, inhibit whole biological function binding to inducing subsequent proteasomal degradation. compensate for limitations transcription factors, nuclear proteins, other scaffolding difficult handle with traditional small-molecule inhibitors. have successfully degraded diverse such BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 ARV-471 exhibited excellent efficacy clinical II trials. However, what appropriate PROTAC achieve better benefits than inhibitors not fully understood. how rationally design an efficient optimize it be orally effective poses big challenges researchers. In this review, we summarize features technology, analyze detail general principles designing PROTACs, discuss typical application different categories. addition, also introduce progress relevant trial results representative assess may face. Collectively, our studies provide references further PROTACs.

Language: Английский

Citations

153
Screening of Potential Inhibitors Targeting the Main Protease Structure of SARS-CoV-2 via Molecular Docking, and Approach with Molecular Dynamics, RMSD, RMSF, H-Bond, SASA and MMGBSA DOI
Aluísio Marques da Fonseca, Bernardino Joaquim Caluaco, Junilson Martinho Canjanja Madureira

et al.

Molecular Biotechnology, Journal Year: 2023, Volume and Issue: 66(8), P. 1919 - 1933

Published: July 25, 2023

Language: Английский

Citations

64
Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules DOI
Christopher M. Hickey, Katherine M. Digianantonio, Kurt Zimmermann

et al.

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(2), P. 311 - 322

Published: Jan. 4, 2024

Language: Английский

Citations

23
Journey of PROTAC: From Bench to Clinical Trial and Beyond DOI

Kyli Berkley,

Julian Zalejski, Nidhi Sharma

et al.

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Proteolysis-targeting chimeras (PROTACs) represent a transformative advancement in drug discovery, offering method to degrade specific intracellular proteins. Unlike traditional inhibitors, PROTACs are bifunctional molecules that target proteins for elimination, enabling the potential treatment of previously "undruggable" This concept, pioneered by Crews and his team, introduced use small link protein an E3 ubiquitin ligase, inducing ubiquitination subsequent degradation protein. By promoting rather than merely inhibiting function, present novel therapeutic strategy with enhanced specificity effectiveness, especially areas such as cancer neurodegenerative diseases. Since their initial field PROTAC research has rapidly expanded numerous now designed wide range disease-relevant The substantial research, investment, collaboration across academia pharmaceutical industry reflect growing interest PROTACs. Review discusses journey from discovery clinical trials, highlighting advancements challenges. Additionally, recent developments fluorescent photogenic PROTACs, used real-time tracking degradation, presented, showcasing evolving targeted therapy.

Language: Английский

Citations

3
Antiviral PROTACs: Opportunity borne with challenge DOI Creative Commons

Jinsen Liang,

Yihe Wu, Ke Lan

et al.

Cell Insight, Journal Year: 2023, Volume and Issue: 2(3), P. 100092 - 100092

Published: March 27, 2023

Proteolysis targeting chimera (PROTAC) degradation of pathogenic proteins by hijacking the ubiquitin-proteasome-system has become a promising strategy in drug design. The overwhelming advantages PROTAC technology have ensured rapid and wide usage, multiple PROTACs entered clinical trials. Several antiviral been developed with bioactivities against various viruses. However, number reported is far less than that other diseases, e.g., cancers, immune disorders, neurodegenerative possibly because common deficiencies (e.g., limited available ligands poor membrane permeability) plus complex mechanism involved high tendency viral mutation during transmission replication, which may challenge successful development effective PROTACs. This review highlights important advances this rapidly growing field critical limitations encountered developing analyzing current status representative examples PROTAC-like agents. We also summarize analyze general principles strategies for design optimization intent indicating potential strategic directions future progress.

Language: Английский

Citations

32
Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL DOI Creative Commons
Digant Nayak, Dongwen Lv, Yaxia Yuan

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 29, 2024

Abstract Overexpression of BCL-xL and BCL-2 play key roles in tumorigenesis cancer drug resistance. Advances PROTAC technology facilitated recent development the first BCL-xL/BCL-2 dual degrader, 753b, a VHL-based degrader with improved potency reduced toxicity compared to previous small molecule inhibitors. Here, we determine crystal structures VHL/753b/BCL-xL VHL/753b/BCL-2 ternary complexes. The two complexes exhibit markedly different architectures that are accompanied by distinct networks interactions at VHL/753b-linker/target interfaces. importance these interfacial contacts is validated via functional analysis informed subsequent rational structure-guided design focused on 753b linker BCL-2/BCL-xL warhead. This results WH244, enhanced degrade cells. Using biophysical assays followed cell activities, able explain target degradation Most PROTACs empirically designed lack structural studies, making it challenging understand their modes action specificity. Our work presents streamlined approach combines structure-based insights backed cell-based studies develop effective PROTAC-based therapeutics.

Language: Английский

Citations

11
Research progress of PROTACs for neurodegenerative diseases therapy DOI

Zhifang Cai,

Zunhua Yang,

Huilan Li

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 147, P. 107386 - 107386

Published: April 18, 2024

Language: Английский

Citations

8
Recent Advances and Future Directions on Small Molecule VEGFR Inhibitors in Oncological Conditions DOI

Amandeep Thakur,

Mandeep Rana,

Anshul Mishra

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 272, P. 116472 - 116472

Published: May 6, 2024

Language: Английский

Citations

8
Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation DOI Creative Commons
Ying Wang, Tianzi Wei,

Man Zhao

et al.

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(5), P. e3002550 - e3002550

Published: May 20, 2024

Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl targeted degradation, we designed and synthesized a series heterobifunctional by conjugating different with bromodomain-containing 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, found these molecules BRD4 through ubiquitin-proteasome system, rather than autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, revealed recruit E3 ubiquitin ligase complex CRL4DCAF11 substrate Furthermore, validated most potent molecule HL435 promising drug-like lead compound exert antitumor activity both in vitro mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties providing possibilities drug discovery.

Language: Английский

Citations

8
PROTAC-induced Protein Structural Dynamics in Targeted Protein Degradation DOI Open Access
Kingsley Y Wu, Ta I Hung, Chia‐en A. Chang

et al.

Published: Jan. 31, 2025

PROteolysis TArgeting Chimeras (PROTACs) are small molecules that induce target protein degradation via the ubiquitin-proteasome system. PROTACs recruit and E3 ligase; a critical first step is forming ternary complex. However, while formation complex crucial, it may not always guarantee successful degradation. The dynamics of PROTAC-induced play key role in ubiquitination subsequent In this study, we computationally modelled structures associated with series featuring different linkers to investigate why these PROTACs, all which formed complexes Cereblon (CRBN) ligase bromodomain-containing 4 (BRD4 BD1 ), exhibited varying degrees potency. We constructed machinery Culling-Ring Ligase 4A (CRL4A) scaffolds. Through atomistic molecular simulations, illustrated how PROTAC-dependent facilitating arrangement surface lysine residues BRD4 into catalytic pocket E2/ubiquitin cascade for ubiquitination. Despite identical warheads PROTAC series, were found affect residue-interaction networks, thus governing essential motions entire machine These findings offer structural dynamic perspective on ligand-induced degradation, providing insights guide future design endeavors.

Language: Английский

Citations

1