The bromodomain inhibitor JQ1 is a molecular glue targeting centromeres DOI Creative Commons
Samuel Corless,

Noor Pratap-Singh,

Nezha S. Benabdallah

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 15, 2023

Centromeres are the position on each chromosome that orchestrates accurate partitioning of genome during cell division. Centromere-dependent cell-cycle checkpoints maintained by cancer cells to prevent catastrophic segregation defects in dividing 1, 2 , making centromeric chromatin a valuable target for anti-cancer therapeutics. However, no compounds have been identified specifically using standard drug discovery approaches. Here we develop big-data approach identify protein composition repetitive DNA loci, including centromeres, and screen candidate small molecules act composition. We discover BET bromodomain BRD4 localises centromeres regulates cohesion. further show inhibitor JQ1 affects stabilising direct interaction between Centromere Protein B (CENP-B), acting as molecular-glue promotes centromere cohesion CENP-B-dependent manner. Strikingly, CENP-B transitions from non-essential JQ1-sensitive most significant determinant cell-proliferation JQ1-resistant cells. Our observations demonstrate completely overlooked role directly targeting centromere, with important consequences JQ1-derivatives currently entering clinical use 3 .

Language: Английский

G protein-coupled receptors (GPCRs): advances in structures, mechanisms and drug discovery DOI Creative Commons
Mingyang Zhang, Ting Chen, Xun Lu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 9, 2024

Abstract G protein-coupled receptors (GPCRs), the largest family of human membrane proteins and an important class drug targets, play a role in maintaining numerous physiological processes. Agonist or antagonist, orthosteric effects allosteric effects, biased signaling balanced signaling, characterize complexity GPCR dynamic features. In this study, we first review structural advancements, activation mechanisms, functional diversity GPCRs. We then focus on discovery by revealing detailed drug-target interactions underlying mechanisms drugs approved US Food Drug Administration past five years. Particularly, up-to-date analysis is performed available structures complexed with synthetic small-molecule modulators to elucidate key receptor-ligand mechanisms. Finally, highlight how widespread GPCR-druggable sites can guide structure- mechanism-based design propose prospects designing bitopic ligands for future therapeutic potential targeting receptor family.

Language: Английский

Citations

118
Expanding the horizons of targeted protein degradation: A non-small molecule perspective DOI Creative Commons
Xiaowei Huang, Fengbo Wu,

Jing Ye

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(6), P. 2402 - 2427

Published: Jan. 21, 2024

Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired PROTAC have not only revolutionized the landscape TPD but potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role this field. wide variety agents spanning broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which prove instrumental overcoming constraints conventional small molecule entities also provided rapidly renewing paradigms. Herein we summarize burgeoning non-small technological platforms PROTACs, three major trajectories, provide insights for design strategies based on novel

Language: Английский

Citations

19
Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies DOI Creative Commons
Xiaopeng Peng, Zhihao Hu,

Limei Zeng

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(2), P. 533 - 578

Published: Sept. 12, 2023

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over past few decades, significant progress has been made development targeted epigenetic modulators (e.g., inhibitors). However, inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack subtype selectivity, drug resistance. As result, design new degraders) such as PROTACs, molecular glue, hydrophobic tagging (HyT) degraders garnered attention from both academia pharmaceutical industry, numerous discovered decade. In this review, we aim to provide an in-depth illustration degrading strategies (2017–2023) targeting proteins for cancer therapy, focusing on rational design, pharmacodynamics, pharmacokinetics, status, crystal structure information these degraders. Importantly, also deep insights into potential challenges corresponding remedies approach development. Overall, hope review will offer better mechanistic understanding serve useful guide emerging epigenetic-targeting

Language: Английский

Citations

28
Activation of human STING by a molecular glue-like compound DOI Creative Commons
Jie Li, Stephen M. Canham, Hua Wu

et al.

Nature Chemical Biology, Journal Year: 2023, Volume and Issue: 20(3), P. 365 - 372

Published: Oct. 12, 2023

Abstract Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation STING requires high-order oligomerization, which could be induced by binding endogenous ligand, cGAMP, cytosolic ligand-binding domain. Here we report discovery through functional screens class compounds, named NVS-STGs, activate STING. Our cryo-EM structures show NVS-STG2 induces oligomerization pocket between domains neighboring dimers, effectively acting as molecular glue. assays showed elicit potent STING-mediated responses cells activities animal models.

Language: Английский

Citations

28
New insights into protein–protein interaction modulators in drug discovery and therapeutic advance DOI Creative Commons
Hossam Nada, Yongseok Choi, Sung-Do Kim

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Dec. 5, 2024

Abstract Protein-protein interactions (PPIs) are fundamental to cellular signaling and transduction which marks them as attractive therapeutic drug development targets. What were once considered be undruggable targets have become increasingly feasible due the progress that has been made over last two decades rapid technological advances. This work explores influence of innovations on PPI research development. Additionally, diverse strategies for discovering, modulating, characterizing PPIs their corresponding modulators examined with aim presenting a streamlined pipeline advancing PPI-targeted therapeutics. By showcasing carefully selected case studies in modulator discovery development, we illustrate efficacy various identifying, optimizing, overcoming challenges associated design. The valuable lessons insights gained from identification, optimization, approval discussed demonstrating transitioned beyond early-stage now represent prime opportunity significant potential. examples encompass those developed cancer, inflammation immunomodulation, well antiviral applications. perspective aims establish foundation effective targeting modulation using pave way future

Language: Английский

Citations

16
Molecular glue degraders: exciting opportunities for novel drug discovery DOI
Thomas Lemaître, Marie Cornu, Florian Schwalen

et al.

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(4), P. 433 - 449

Published: Jan. 19, 2024

Introduction Molecular Glue Degraders (MGDs) is a concept that refers to class of compounds facilitate the interaction between two proteins or molecules within cell. These act as bridge enhances specific Protein-Protein Interactions (PPIs). Over past decade, this technology has gained attention potential strategy target were traditionally considered undruggable using small molecules.

Language: Английский

Citations

10
Identification and characterization of ternary complexes consisting of FKBP12, MAPRE1 and macrocyclic molecular glues DOI Creative Commons
Michael Salcius, Antonin Tutter, Marianne Fouché

et al.

RSC Chemical Biology, Journal Year: 2025, Volume and Issue: 6(5), P. 788 - 799

Published: Jan. 1, 2025

Many disease-relevant and functionally well-validated targets are difficult to drug. Their poorly defined 3D structure without deep hydrophobic pockets makes the development of ligands with low molecular weight high affinity almost impossible. For these targets, incorporation into a ternary complex may be viable alternative modulate in most cases inhibit their function. Therefore, we interested methods identify characterize glues. In protein array screen 50 different macrocyclic FKBP12 against 2500 randomly selected proteins, glue compound was found recruit dimeric called MAPRE1 compound-dependent manner. The corresponding characterized by TR-FRET proximity assay native MS spectroscopy. Insights were obtained 2D NMR spectroscopy finally an X-ray structure, which revealed as 2 : exhibiting multiple interactions that occur exclusively lead significant cooperativity α. Using rationally guided synthesis series analogues led driven improvement stability complex. Furthermore, formation confirmed cellular NanoBiT assays, whose A max values correlate those from assay. experiments showed functional impact (inhibition) glues on interaction its intracellular partners.

Language: Английский

Citations

1
Recent advances in regulating the cell cycle through inhibiting CDKs for cancer treatment DOI

Weijiao Chen,

Xujie Zhuang, Yuanyuan Chen

et al.

Chinese Journal of Natural Medicines, Journal Year: 2025, Volume and Issue: 23(3), P. 286 - 298

Published: March 1, 2025

Language: Английский

Citations

1
Biomimetic Synthesis and Chemical Proteomics Reveal the Mechanism of Action and Functional Targets of Phloroglucinol Meroterpenoids DOI

Amy K. Bracken,

Colby E. Gekko,

Nina O. Suss

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(4), P. 2524 - 2548

Published: Jan. 17, 2024

Natural products perennially serve as prolific sources of drug leads and chemical probes, fueling the development numerous therapeutics. Despite their scarcity, natural that modulate protein function through covalent interactions with lysine residues hold immense potential to unlock new therapeutic interventions advance our understanding biological processes governed by these modifications. Phloroglucinol meroterpenoids constitute one most expansive classes products, displaying a plethora activities. However, mechanism action cellular targets have, until now, remained elusive. In this study, we detail concise biomimetic synthesis, computational mechanistic insights, physicochemical attributes, kinetic parameters, molecular action, functional several phloroglucinol meroterpenoids. We harness synthetic clickable analogues probe disparate proteome-wide reactivity subcellular localization in-gel fluorescence scanning cell imaging. By implementing sample multiplexing redesigned lysine-targeting probe, streamline quantitative activity-based profiling, enabling direct mapping global ligandability proteinaceous lysines in human cells. Leveraging framework, identify lysine–meroterpenoid breast cancer cells at tractable sites across diverse structural classes, including those historically deemed undruggable. validate perturb biochemical functions stereoselective site-specific modification proteins vital for metabolism, lipid signaling, mitochondrial respiration, glycolysis. These findings underscore broad targeting proteome.

Language: Английский

Citations

7
Targeting the STAT3 pathway with STAT3 degraders DOI
Zhijie Wang,

Xiaotong Liao,

Haiqi He

et al.

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(9), P. 811 - 823

Published: Aug. 7, 2024

Language: Английский

Citations

7