Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Сен. 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.

Язык: Английский

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Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(10), С. 7668 - 7758

Опубликована: Май 7, 2024

Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with variety new targeted drugs having been approved recent years. A key feature such molecules is an intrinsically reactive group, typically weak electrophile, which enables irreversible or reversible formation bond specific amino acid target protein. This often called "warhead", critical determinant ligand's activity, selectivity, general biological properties. In 2019, we summarized emerging re-emerging warhead chemistries to cysteine acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 62, 5673−5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, field has rapidly evolved. Here discuss progress on warheads made since our last Perspective their application medicinal chemistry chemical biology.

Язык: Английский

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Inhibition of Autophagy by a Small Molecule through Covalent Modification of the LC3 Protein

Angewandte Chemie International Edition, Год журнала: 2021, Номер 60(50), С. 26105 - 26114

Опубликована: Сен. 30, 2021

Abstract The autophagic ubiquitin‐like protein LC3 functions through interactions with LC3‐interaction regions (LIRs) of other autophagy proteins, including receptors, which stands out as a promising protein–protein interaction (PPI) target for the intervention autophagy. Post‐translational modifications like acetylation Lys49 on LIR‐interacting surface could disrupt interaction, offering an opportunity to design covalent small molecules interfering interface. Through screening compounds, we discovered molecule modulator LC3A/B that covalently modifies at Lys49. Activity‐based profiling (ABPP) based evaluations reveal derivative DC‐LC3in‐D5 exhibits potent reactivity and selectivity in HeLa cells. compromises LC3B lipidation vitro cells, leading deficiency formation structures substrate degradation. serve powerful tool research well therapeutic interventions.

Язык: Английский

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2-Ethynylbenzaldehyde-Based, Lysine-Targeting Irreversible Covalent Inhibitors for Protein Kinases and Nonkinases

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(7), С. 3844 - 3849

Опубликована: Фев. 12, 2023

Lysine-targeting irreversible covalent inhibitors have attracted growing interests in recent years, especially the fields of kinase research. Despite encouraging progress, few chemistries are available to develop that exclusively lysine-targeting, selective, and cell-active. We report herein a 2-ethynylbenzaldehyde (EBA)-based, lysine-targeting strategy generate potent selective small-molecule ABL by selectively targeting conserved catalytic lysine enzyme. showed resulting compounds were cell-active, capable covalently engaging endogenous K562 cells with long-residence time off-targets. further validated generality this developing EBA-based against EGFR (a kinase) Mcl-1 nonkinase) reacted noncatalytic within each target.

Язык: Английский

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Global Reactivity Profiling of the Catalytic Lysine in Human Kinome for Covalent Inhibitor Development

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(12)

Опубликована: Янв. 22, 2024

Abstract Advances in targeted covalent inhibitors (TCIs) have been made by using lysine‐reactive chemistries. Few aminophiles possessing balanced reactivity/stability for the development of cell‐active TCIs are however available. We report herein activity‐based probes (ABPs; 2–14 ) based on chemistry aryl fluorosulfates (ArOSO 2 F) capable global reactivity profiling catalytic lysine human kinome from mammalian cells. concurrently developed reversible ABPs ( 15 / 16 installing salicylaldehydes (SA) onto a promiscuous kinase‐binding scaffold. The stability and amine these exhibited broad range tunability. X‐ray crystallography mass spectrometry (MS) confirmed successful engagement between ArOSO F 9 SRC kinase. Chemoproteomic studies enabled >300 endogenous kinases, thus providing landscape ligandable lysines kinome. By further introducing into VX‐680 (a noncovalent inhibitor AURKA kinase), we generated novel that excellent vitro potency reasonable cellular activities with prolonged residence time. Our work serves as general guide F‐based TCIs.

Язык: Английский

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Recent progress in covalent warheads for in vivo targeting of endogenous proteins

Bioorganic & Medicinal Chemistry, Год журнала: 2021, Номер 47, С. 116386 - 116386

Опубликована: Авг. 27, 2021

Язык: Английский

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Sulfamate Acetamides as Self-Immolative Electrophiles for Covalent Ligand-Directed Release Chemistry

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(6), С. 3346 - 3360

Опубликована: Фев. 4, 2023

Electrophiles for covalent inhibitors that are suitable in vivo administration rare. While acrylamides prevalent FDA-approved drugs, chloroacetamides considered too reactive such purposes. We report sulfamate-based electrophiles maintain chloroacetamide-like geometry with tunable reactivity. In the context of BTK inhibitor ibrutinib, sulfamate analogues showed low reactivity comparable potency protein labeling, vitro, and cellular kinase activity assays were effective a mouse model CLL. second example, we converted chloroacetamide Pin1 to potent selective acetamide improved buffer stability. Finally, show acetamides can be used ligand-directed release (CoLDR) chemistry, both generation "turn-on" probes as well traceless site-specific labeling proteins. Taken together, this chemistry represents promising addition list targeting.

Язык: Английский

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Platform Reagents Enable Synthesis of Ligand-Directed Covalent Probes: Study of Cannabinoid Receptor 2 in Live Cells

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(28), С. 15094 - 15108

Опубликована: Июль 4, 2023

Pharmacological modulation of cannabinoid receptor type 2 (CB2R) holds promise for the treatment neuroinflammatory disorders, such as Alzheimer's disease. Despite importance CB2R, its expression and downstream signaling are insufficiently understood in disease- tissue-specific contexts. Herein, we report first ligand-directed covalent (LDC) labeling CB2R enabled by a novel synthetic strategy application platform reagents. The LDC modification allows visualization study while maintaining ability to bind other ligands at orthosteric site. We employed silico docking molecular dynamics simulations guide probe design assess feasibility CB2R. demonstrate selective, peripheral lysine residue exploiting fluorogenic O-nitrobenzoxadiazole (O-NBD)-functionalized probes TR-FRET assay. rapid proof-of-concept validation with O-NBD inspired incorporation advanced electrophiles suitable experiments live cells. To this end, strategies toward N-sulfonyl pyridone (N-SP) N-acyl-N-alkyl sulfonamide (NASA) were developed, which allowed delivery fluorophores cellular studies. characterized radioligand binding assay experiments. Additionally, applied specifically visualize conventional imaging flow cytometry well confocal fluorescence microscopy using overexpressing endogenously expressing microglial

Язык: Английский

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Formation of mono- and dual-labelled antibody fragment conjugates via reversible site-selective disulfide modification and proximity induced lysine reactivity

Chemical Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Exploiting quantitative and reversible site-selective disulfide modification as a means for selective lysine functionalisation on clinically relevant antibody fragments.

Язык: Английский

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Targeted Covalent Modification Strategies for Drugging the Undruggable Targets

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

The term "undruggable" refers to proteins or other biological targets that have been historically challenging target with conventional drugs therapeutic strategies because of their structural, functional, dynamic properties. Drugging such undruggable is essential develop new therapies for diseases where current treatment options are limited nonexistent. Thus, investigating methods achieve drugging an important challenge in medicinal chemistry. Among the numerous methodologies drug discovery, covalent modification has emerged as a transformative strategy. attachment diverse functional molecules provides powerful platform creating highly potent and chemical tools well ability provide valuable information on structures dynamics targets. In this review, we summarize recent examples biomolecules development therapeutics overcome discovery challenges highlight how contribute toward particular, focus use chemistry drugs, identification, screening, artificial modulation post-translational modifications, cancer specific chemotherapies, nucleic acid-based therapeutics.

Язык: Английский

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