Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants DOI Creative Commons
Anne E. van Vlimmeren, Lauren C. Tang, Ziyuan Jiang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Abstract Missense mutations in PTPN11 , the gene encoding protein tyrosine phosphatase SHP2, are common several developmental disorders and cancers. While many SHP2 disrupt auto-inhibition cause hyperactivity, do not enhance catalytic activity. Both activating non-activating could potentially drive pathogenic signaling by altering protein-protein interactions or subcellular localization. We employed proximity-labeling proteomics to map interaction networks of wild-type ten clinically-relevant mutants, bound an inhibitor that stabilizes its auto-inhibited state. Our analyses revealed mutation-and inhibitor-dependent alterations interactome, with mutants also showing changes In particular, some had increased mitochondrial localization impacted function. This study provides a rich resource for exploring offers new insights into molecular basis SHP2-driven diseases. Furthermore, this work highlights capacity detect missense-mutation-dependent

Language: Английский

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials DOI Creative Commons
Xin Xie, Tingting Yu, Xiang Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 6, 2023

Abstract Undruggable proteins are a class of that often characterized by large, complex structures or functions difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also great opportunity for treatment human diseases and attracted substantial efforts in the field medicine. Therefore, this review, we focus on recent development discovery targeting “undruggable” their application clinic. To make review well organized, discuss strategies proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction targeted nucleic acid-based approach, immunotherapy others.

Language: Английский

Citations

166
Targeting the undruggables—the power of protein degraders DOI Creative Commons
Chao Zhang, Yongbo Liu, Guangchen Li

et al.

Science Bulletin, Journal Year: 2024, Volume and Issue: 69(11), P. 1776 - 1797

Published: March 29, 2024

Undruggable targets typically refer to a class of therapeutic that are difficult target through conventional methods or have not yet been targeted, but great clinical significance. According statistics, over 80% disease-related pathogenic proteins cannot be targeted by current treatment methods. In recent years, with the advancement basic research and new technologies, development various technologies mechanisms has brought perspectives overcome challenging drug targets. Among them, protein degradation technology is breakthrough strategy for This can specifically identify directly degrade utilizing inherent pathways within cells. form includes types such as proteolysis targeting chimera (PROTAC), molecular glue, lysosome-targeting Chimaera (LYTAC), autophagosome-tethering compound (ATTEC), autophagy-targeting (AUTAC), (AUTOTAC), degrader-antibody conjugate (DAC). article systematically summarizes application in degraders Finally, looks forward future direction prospects technology.

Language: Английский

Citations

22
Optogenetics with Atomic Precision─A Comprehensive Review of Optical Control of Protein Function through Genetic Code Expansion DOI Creative Commons
Maura E. Charette,

Carolyn Rosenblum,

Olivia Shade

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Conditional control of protein activity is important in order to elucidate the particular functions and interactions proteins, their regulators, substrates, as well impact on behavior a cell or organism. Optical provides perhaps optimal means introducing spatiotemporal over function it allows for tunable, rapid, noninvasive activation its native environment. One method optical through introduction photocaged photoswitchable noncanonical amino acids (ncAAs) genetic code expansion cells animals. Genetic incorporation photoactive ncAAs at key residues tool activation, sometimes deactivation, activity. Importantly, site can typically be rationally selected based structural, mechanistic, computational information. In this review, we comprehensively summarize applications lysine, tyrosine, cysteine, serine, histidine, glutamate, aspartate derivatives, phenylalanine analogues. The extensive diverse list proteins that have been placed under demonstrates broad applicability methodology.

Language: Английский

Citations

2
Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors DOI
Alexander M. Taylor, Bret R. Williams, Fabrizio Giordanetto

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(19), P. 13384 - 13399

Published: Sept. 29, 2023

Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest oncology, both for treating with single agent combination KRAS inhibitor. We were drawn to the pharmacological potential inhibition, especially following initial observation that drug-like compounds could bind an allosteric site enforce closed, inactive state enzyme. Here, we describe identification characterization GDC-1971 (formerly RLY-1971), inhibitor currently clinical trials G12C divarasib (GDC-6036) treatment solid tumors driven by mutation.

Language: Английский

Citations

27
Macrophage SHP2 Deficiency Alleviates Diabetic Nephropathy via Suppression of MAPK/NF-κB– Dependent Inflammation DOI
Xue Han, Jiajia Wei,

Ruyi Zheng

et al.

Diabetes, Journal Year: 2024, Volume and Issue: 73(5), P. 780 - 796

Published: Feb. 23, 2024

Increasing evidence implicates chronic inflammation as the main pathological cause of diabetic nephropathy (DN). Exploration key targets in inflammatory pathway may provide new treatment options for DN. We aimed to investigate role Src homology 2–containing protein tyrosine phosphatase 2 (SHP2) macrophages and its association with The upregulated phosphorylation SHP2 was detected both patients diabetes a mouse model. Using macrophage-specific SHP2-knockout (SHP2-MKO) mice SHP2fl/fl injected streptozotocin (STZ), we showed that SHP2-MKO significantly attenuated renal dysfunction, collagen deposition, fibrosis, response STZ-induced diabetes. RNA-sequencing analysis using primary peritoneal (MPMs) deletion mainly affected mitogen-activated kinase (MAPK) nuclear factor-κB (NF-κB) signaling pathways well MAPK/NF-κB–dependent cytokine release MPMs. Further study indicated SHP2-deficient failed cytokines induce phenotypic transition fibrosis cells. Administration pharmacological inhibitor, SHP099, remarkably protected kidneys type 1 mice. In conclusion, these results identify macrophage accelerator DN suggest inhibition be therapeutic option Article Highlights

Language: Английский

Citations

10
Protein kinase A suppresses anti-proliferative effect of interferon-α in hepatocellular carcinoma by activation of protein tyrosine phosphatase SHP2 DOI Creative Commons

Yuwen Sheng,

Yuan Lin, Zhe Qiang

et al.

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108195 - 108195

Published: Jan. 1, 2025

Language: Английский

Citations

1
SH2 Domains: Folding, Binding and Therapeutical Approaches DOI Open Access
Awa Diop,

Daniele Santorelli,

Francesca Malagrinò

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(24), P. 15944 - 15944

Published: Dec. 15, 2022

SH2 (Src Homology 2) domains are among the best characterized and most studied protein-protein interaction (PPIs) modules able to bind recognize sequences presenting a phosphorylated tyrosine. This post-translational modification is key regulator of plethora physiological molecular pathways in eukaryotic cell, so possess fundamental role cell signaling. Consequently, several pathologies arise from dysregulation such SH2-domains mediated PPIs. In this review, we recapitulate current knowledge about structural, folding stability, binding properties their roles pathogenesis. Moreover, focus attention on different strategies employed modulate/inhibit binding. Altogether, information gathered points evidence that pharmacological interest highly strategic developing new therapeutics. deeper understanding determinants thermodynamic stability as well appears be order improve possibility preventing dysregulated interactions.

Language: Английский

Citations

37
Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure DOI Open Access
Victor Hugo Fonseca de Jesus, Maria Cecília Mathias-Machado,

João Paulo Fogacci de Farias

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(20), P. 5015 - 5015

Published: Oct. 17, 2023

Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer-related mortality, and it is expected to play even bigger part in cancer burden the years come. Despite concerted efforts from scientists physicians, patients have experienced little improvement survival over past decades, possibly because non-specific nature tested treatment modalities. Recently, discovery potentially targetable molecular alterations has paved way for personalized PDAC. Indeed, central piece framework PDAC starting be unveiled. KRAS mutations are seen 90% PDACs, multiple studies demonstrated their pivotal role pancreatic carcinogenesis. Recent investigations shed light on differences prognosis as well therapeutic implications different disentangled relationship between effectors downstream parallel signaling pathways. Additionally, recognition other mechanisms involving KRAS-mediated pathogenesis, such dosing allelic imbalance, contributed broadening current knowledge regarding this alteration. Finally, G12C inhibitors been recently with relative success, harboring under clinical development. These drugs currently represent a true hope meaningful leap forward dreadful disease.

Language: Английский

Citations

18
Targeted protein degradation using chimeric human E2 ubiquitin-conjugating enzymes DOI Creative Commons
Jonathan D. Taylor,

Nathalie Barrett,

Sergio Martínez Cuesta

et al.

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Sept. 19, 2024

Language: Английский

Citations

8
Traditional Chinese medicine inhibits PD-1/PD-L1 axis to sensitize cancer immunotherapy: a literature review DOI Creative Commons

Huilan Zheng,

Gang Wang, Ming Liu

et al.

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: June 16, 2023

The Programmed death-1 (PD-1) and its programmed death-ligand 1 (PD-L1) comprise the PD-1/PD-L1 axis maintain tumor immune evasion. Cancer immunotherapy based on anti-PD-1/PD-L1 antibodies is most promising anti-tumor treatment available but currently facing thorny problem of unsatisfactory outcomes. Traditional Chinese Medicine (TCM), with rich heritage medicine monomers, herbal formulas, physical therapies like acupuncture, moxibustion, catgut implantation, a multi-component multi-target system known for enhancing immunity preventing spread disease. TCM often used as an adjuvant therapy cancer in clinical practices, recent studies have demonstrated synergistic effects combining immunotherapy. In this review, we examined role escape while exploring how can modulate to improve efficacy Our findings suggest that enhance by reducing expression PD-1 PD-L1, regulating T-cell function, improving microenvironment, intestinal flora. We hope review may serve valuable resource future sensitization checkpoint inhibitors (ICIs) therapy.

Language: Английский

Citations

14