Next steps for targeted protein degradation

Cell chemical biology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Язык: Английский

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Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of action elucidation and in vivo proof of concept

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

Abstract Prospective discovery of molecular glues degraders for a specific therapeutic target protein interest is an emerging strategy in drug discovery. Modification pre-existing ligands with fragments that can alter the surface lead to creation novel compounds (‘’targeted glues’’) able induce neo-interactions between and E3 ligase, resulting targeted degradation. By screening library potential BRD9 glue compounds, we have discovered potent selective, reversibly covalent degrader, AMPTX-1 . Co-immunoprecipitation-mass spectrometry experiments demonstrated cell treatment induces selective recruitment ligase DCAF16. Degradation dependent on engagement Cys58 DCAF16 formation adduct facilitated by ternary complex BRD9. degradation achieved viv o after oral dosing, demonstrating viable be drug-like, orally bioavailable promising vivo activity.

Язык: Английский

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Use of Aldehyde–Alkyne–Amine Couplings to Generate Medicinal Chemistry-Relevant Linkers

ACS Medicinal Chemistry Letters, Год журнала: 2025, Номер unknown

Опубликована: Янв. 25, 2025

Copper catalyzed aldehyde–alkyne–amine (A3) couplings lead to multifunctional, racemic, propargylic amines, many on a multigram scale. As part of an industrial collaboration, selection linkers was purified by chiral HPLC afford single enantiomers, the absolute configuration which determined vibrational circular dichroism (vCD). To show medicinal chemistry applications, selected were further derivatized into potential cellular probes and (+)-JQ1 containing PROTACs (proteolysis targeting chimeras), degraded their target protein BRD4.

Язык: Английский

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Discovery of a Series of Covalent Ligands That Bind to Cys77 of the Von Hippel–Lindau Tumor Suppressor Protein (VHL)

ACS Medicinal Chemistry Letters, Год журнала: 2025, Номер 16(4), С. 693 - 699

Опубликована: Март 19, 2025

Most ligands for the Von Hippel-Lindau tumor suppressor (VHL) bind at HIF-1α binding site. Ligands that to allosteric sites on VHL could be highly valuable field of protein degradation, therefore, a covalent hit identification campaign was run targeting Cys77 VHL. Hit 2 bound selectively and did not alkylate reactive Cys89 Elongin B. It showed time- concentration-dependent labeling, with k inact/K I 0.30 M-1 s-1, does affect This ligand optimized afford compound 15 which improved potency labeling An X-ray structure close analogue determined revealing in shallow groove surface These are first small molecules covalently an site provide suitable starting point further optimization.

Язык: Английский

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Razing the Scaffolding: The Elimination of Non-Catalytic Functions of Kinases through Targeted Protein Degradation

RSC Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Overexpression and activation of kinases often results in cancer initiation progression through both catalytic non-catalytic functions by promoting rapid proliferation, growth, survival, metastasis cells. Catalytic functions...

Язык: Английский

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Targeted protein degradation for cancer therapy

Nature reviews. Cancer, Год журнала: 2025, Номер unknown

Опубликована: Апрель 25, 2025

Язык: Английский

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Targeted Protein Degradation of Metalloenzymes

Burger's Medicinal Chemistry and Drug Discovery, Год журнала: 2025, Номер unknown, С. 1 - 45

Опубликована: Май 26, 2025

Abstract The field of targeted protein degradation (TPD) has expanded rapidly in the last decade. However, only a handful metal‐dependent enzymes (metalloenzymes) have been target these efforts. chapter gives an overview TPD as it applied to metalloenzymes and highlights key findings. relevant bioinorganic chemistry approaches, including metal‐binding pharmacophores (MBPs) used degraders, will be particular emphasis this review.

Язык: Английский

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Recent advances in dual PROTACs degrader strategies for disease treatment

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 279, С. 116901 - 116901

Опубликована: Сен. 27, 2024

Язык: Английский

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Advances in Targeted Therapies for Inflammatory Diseases and Cancer: Exploring Cellular Mechanisms and Therapeutic Strategies

ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 15(6), С. 758 - 760

Опубликована: Май 8, 2024

Managing chronic inflammatory diseases and cancers has traditionally faced challenges due to the complexity of disease mechanisms often-insufficient specificity treatments. This Patent Highlight showcases findings from three innovative patents that propose distinct yet complementary therapeutic strategies modulate key cellular processes involved in inflammation cancer progression. The first strategy involves proteolysis targeting chimeras (PROTACs) for selective degradation IRAK4, a kinase central signaling, second employs lipid-binding protein complexes systemic responses, third utilizes inhibitors pathogenic epithelial stem cells prevent progression metaplasia into dysplasia cancer. Collectively, these approaches highlight shift toward precision medicine, offering potential synergistic applications clinical settings.

Язык: Английский

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Tumor Biology Hides Novel Therapeutic Approaches to Diffuse Large B-Cell Lymphoma: A Narrative Review

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(21), С. 11384 - 11384

Опубликована: Окт. 23, 2024

Diffuse large B-cell lymphoma (DLBCL) is a malignancy of immense biological and clinical heterogeneity. Based on the transcriptomic or genomic approach, several different classification schemes have evolved over years to subdivide DLBCL into clinically (prognostically) relevant subsets, but each leaves unclassified samples. Herein, we outline tumor biology behind actual potential drug targets address challenges drawbacks coupled with their (potential) use. Therapeutic modalities are discussed, including small-molecule inhibitors, naked antibodies, antibody-drug conjugates, chimeric antigen receptors, bispecific antibodies T-cell engagers, immune checkpoint inhibitors. Candidate drugs explored in ongoing trials diverse toxicity issues refractoriness drugs. According literature DLBCL, promise for new therapeutic lies epigenetic alterations, receptor NF-κB pathways. present putative hiding lipid pathways, ferroptosis, gut microbiome that could be used addition immuno-chemotherapy improve general health status patients, thus increasing chance being cured. It may time devote more effort exploring metabolism discover novel druggable targets. We also performed bibliometric knowledge-map analysis published from 2014-2023.

Язык: Английский

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