G3BP1/2-Targeting PROTAC Disrupts Stress Granules Dependent ATF4 Migracytosis as Cancer Therapy DOI
Ting Dong, Fabao Zhao,

Mengmeng Wang

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 22, 2024

Stress granules (SGs) are membraneless cytoplasmic compartments that form in response to stress stimuli. In these compartments, most translation factors stall, except for activating transcription factor 4 (ATF4), which is preferentially translated ensure cell survival under stressful conditions. Cancer cells encounter various conditions the tumor microenvironment during tumorigenesis; however, how they exploit pro-survival effects of ATF4 SGs remains unclear. G3BP1/2 central nodes SG network, regulating dynamics. this study, we designed two small molecules, #129 and PROTAC (Proteolysis Targeting Chimera) degrader 129 (PT-129), specifically target NTF2L domain G3BP1/2, a crucial hub protein RNA interactions. These compounds inhibit formation stressed disassemble pre-existing granules. Furthermore, pharmacological inhibition by PT-129 suppressed fibroblast-mediated cancer growth vitro reduced vivo. Mechanistically, facilitates delivery from fibroblasts via migracytosis, primary mediator fibroblast-associated growth. PT-129-mediated disassembly disrupts delivery, thereby preventing proliferation. compounds, therefore, represent powerful tools gaining molecular insights into hold promise therapeutic interventions modulating granule

Language: Английский

Finding a needle in the haystack: ADME and pharmacokinetics/pharmacodynamics characterization and optimization toward orally available bifunctional protein degraders DOI
Giulia Apprato, Giulia Caron, Gauri Deshmukh

et al.

Expert Opinion on Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 16, 2025

Degraders are an increasingly important sub-modality of small molecules as illustrated by ever-expanding number publications and clinical candidate in human trials. Nevertheless, their preclinical optimization ADME PK/PD properties has remained challenging. Significant research efforts being directed to elucidate underlying principles derive rational strategies. In this review the authors summarize current best practices terms vitro assays vivo experiments. Furthermore, collate comment on understanding optimal physicochemical characteristics impact absorption, distribution, metabolism excretion including knowledge Drug-Drug interactions. Finally, describe Pharmacokinetic prediction Pharmacokinetic/Pharmacodynamic -concepts unique degraders how implement these projects. Despite many recent advances field, continued will further our design regarding degrader optimization. Machine-learning computational approaches become once larger, more robust datasets available. tissue-targeting (particularly Central Nervous System be studied efficacious drug regimens that capitalize catalytic mode action. additional specialized (e.g. covalent degraders, LOVdegs) can enrich field offer interesting alternative approaches.

Language: Английский

Citations

1
Delineating cysteine-reactive compound modulation of cellular proteostasis processes DOI
Ashley R. Julio, Flowreen Shikwana,

Cindy Truong

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 24, 2024

Language: Английский

Citations

7
Identification of actionable targeted protein degradation effector sites through Site-specific Ligand Incorporation-induced Proximity (SLIP) DOI Creative Commons
Zhangping Xiao,

Efthymios Spyridon Gavriil,

Fangyuan Cao

et al.

Published: Feb. 4, 2025

ABSTRACT Targeted protein degradation (TPD) is a rapidly emerging and potentially transformative therapeutic modality. However, the large majority of >600 known ubiquitin ligases have yet to be exploited as TPD effectors by proteolysis-targeting chimeras (PROTACs) or molecular glue degraders (MGDs). We report here chemical–genetic platform, Site-specific Ligand Incorporation-induced Proximity (SLIP), identify actionable (“PROTACable”) sites on any potential effector in intact cells. SLIP uses genetic code expansion (GCE) encode copper-free “click” ligation at specific site cells, enabling situ formation covalent PROTAC-effector conjugate against target interest (POI). Modification drives targeted protein, establishing these for TPD. Using SLIP, we systematically screened dozens across E3 E2 enzymes from diverse classes, identifying multiple novel PROTACable which are competent adds powerful approach proximity-induced pharmacology (PIP) toolbox, future ligand discovery fully enable TPD, other PIP modalities.

Language: Английский

Citations

0
Computational approaches to aid PROTAC drug discovery DOI

Sohini Chakraborti,

Kirsten McAulay

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
The Role of ETS2 in Macrophage Inflammation DOI
Christina T. Stankey, James Lee

DNA and Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

Autoimmune and inflammatory diseases are rising globally yet widely effective therapies remain elusive. Most treatments have limited efficacy, significant potential side effects, or eventually lose response, underscoring the urgent need for new therapeutic approaches. We recently discovered that ETS2, a transcription factor, functions as master regulator of macrophage-driven inflammation-and is causally linked to pathogenesis multiple via human genetics. The pleotropic effects ETS2 included upregulation many cytokines individually targeted by current disease therapies, including TNFα, IL-23, IL1β, TNF-like ligand 1A signaling. With move toward combination treatment-to maximize efficacy-targeting presents unique opportunity potentially induce broad effect. However, there will be challenges overcome since direct inhibition unlikely feasible. Here, we discuss these other unanswered questions about central role plays in macrophage inflammation.

Language: Английский

Citations

0
Targeted Protein Degradation: From Basic Science to Therapeutic Applications DOI
R Zhu, Xiaoyu Tang, Heng Zhang

et al.

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

Published: April 18, 2025

Targeted protein degradation (TPD) is a groundbreaking approach in molecular therapeutics, enabling the selective elimination of specific proteins by leveraging cell's own machinery. In November 2024, SMART Symposium titled "Targeted Protein Degradation: from basic science to therapeutic applications" offered comprehensive communication on cutting-edge chemical strategies and emerging clinical applications this rapidly advancing field.

Language: Английский

Citations

0
Development of Ligands and Degraders Targeting MAGE-A3 DOI
Ke Li, Mackenzie W. Krone,

Arseniy Butrin

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(36), P. 24884 - 24891

Published: Aug. 27, 2024

Type I melanoma antigen (MAGE) family members are detected in numerous tumor types, and expression is correlated with poor prognosis, high grade, increased metastasis. MAGE proteins typically restricted to reproductive tissues, but can recur during tumorigenesis. Several biochemical functions have been elucidated for them, notably, MAGEs regulate proteostasis by serving as substrate recognition modules E3 ligase complexes. The repertoire of complexes that be hijacked targeted protein degradation continues expand, MAGE-E3 an especially attractive platform given their cancer-selective expression. Additionally, type MAGE-derived peptides presented on cancer cell surfaces, so may increase presentation improve immunotherapy outcomes. Motivated these applications, we developed novel, small-molecule ligands MAGE-A3, a widely expressed tumors associates TRIM28, RING ligase. Chemical matter was identified through DNA-encoded library (DEL) screening, hit compounds were validated

Language: Английский

Citations

3
Asymmetric Dirhodium-Catalyzed Modification of Immunomodulatory Imide Drugs and Their Biological Assessment DOI Creative Commons
William F. Tracy, Geraint H. M. Davies, Lei Jia

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(9), P. 1575 - 1583

Published: Aug. 23, 2024

Cereblon (CRBN) has been successfully co-opted to affect the targeted degradation of "undruggable" proteins with immunomodulatory imide drugs (IMiDs). IMiDs act as molecule glues that facilitate ternary complex formation between CRBN and a target protein, leading ubiquitination proteasomal degradation. Subtle structural modifications often cause profound sometimes unpredictable changes in selectivity. Herein, we utilize enantioselective cyclopropanation cyclopropenation on intact glutarimides enable preparation stereochemically regiochemically matched molecular pairs for structure–activity relationship (SAR) analysis across several classical neosubstrates. The resulting glutarimide analogs were found reside unique chemical space when compared other public domain. SAR studies revealed that, addition more precedented impacts regiochemistry, stereochemical far from can lead divergent neosubstrate These findings emphasize importance enabling methods glutarimide-containing compounds tune

Language: Английский

Citations

2
Monovalent Pseudo-Natural Product Degraders Supercharge the Native Degradation of IDO1 by KLHDC3 DOI Creative Commons

Elisabeth Hennes,

Belén Lucas,

Natalie S. Scholes

et al.

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

Published: July 13, 2024

Targeted protein degradation (TPD) modulates function beyond inhibition of enzyme activity or protein-protein interactions. Most degraders by proximity induction, and directly bridge an E3 ligase with the target to be degraded. However, many proteins might not addressable via proximity-based degraders, other challenges, such as resistance acquisition, exist. Here, we identified pseudo-natural products derived from (-)-myrtanol, termed iDegs, that inhibit induce immunomodulatory indoleamine-2,3-dioxygenase 1 (IDO1) a distinct mechanism. iDegs unique conformational change and, thereby, boost IDO1 ubiquitination cullin-RING CRL2

Language: Английский

Citations

2
Property-based optimisation of PROTACs DOI
James S. Scott, Iacovos N. Michaelides, Markus Schade

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

PROTACs are an emerging therapeutic approach towards targeted protein degradation. This article examines the leading examples of this modality that in clinical development through prism their physicochemical properties.

Language: Английский

Citations

2