Redirecting the pioneering function of FOXA1 with covalent small molecules

Molecular Cell, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Язык: Английский

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Redox regulation: mechanisms, biology and therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Март 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Язык: Английский

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Functional implications of fumarate-induced cysteine succination

Trends in Biochemical Sciences, Год журнала: 2024, Номер 49(9), С. 775 - 790

Опубликована: Июнь 13, 2024

Mutations in metabolic enzymes are associated with hereditary and sporadic forms of cancer. For example, loss-of-function mutations affecting fumarate hydratase (FH), the tricarboxylic acid (TCA) cycle enzyme, result accumulation millimolar levels that cause an aggressive form kidney A distinct feature is its ability to spontaneously react thiol groups cysteines a chemical reaction termed succination. Although succination few proteins has been causally implicated molecular features FH-deficient cancers, stoichiometry, wider functional consequences, contribution disease development remain largely unexplored. We discuss implications fumarate-induced cells, available methodologies, current challenges studying this post-translational modification.

Язык: Английский

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Covalent fragment-based drug discovery for target tractability

Current Opinion in Structural Biology, Год журнала: 2024, Номер 86, С. 102809 - 102809

Опубликована: Март 29, 2024

An important consideration in drug discovery is the prioritization of tractable protein targets that are not only amenable to binding small molecules, but also alter disease biology response molecule binding. Covalent fragment-based has emerged as a powerful approach aid identification such targets. The application irreversible mechanisms enables fragment hits for challenging-to-target proteins, allows proteome-wide screening cellular context, and makes it possible determine functional effects with modestly potent ligands without requirement extensive compound optimization. Here, we provide an overview recent approaches covalent discuss how these have been applied establish tractability unexplored sites on

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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Proteomic Ligandability Maps of Phosphorus(V) Stereoprobes Iden-tify Covalent TLCD1 Inhibitors

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

Опубликована: Янв. 31, 2025

ABSTRACT Activity-based protein profiling (ABPP) of stereoisomerically defined sets electrophilic compounds (‘stereoprobes’) offers a versatile way to discover covalent ligands for proteins in native biological systems. Here we report the synthesis and chemical proteomic characterization stereoprobes bearing P(V)-oxathiaphospholane (OTP) reactive group. ABPP experiments identified numerous human cancer cells that showed stereoselective reactivity with OTP stereoprobes, confirmed several these liganding events recombinant proteins. engaging poorly characterized transmembrane TLCD1 impaired incorporation monounsaturated fatty acids into phosphatidylethanolamine lipids cells, lipidomic phenotype mirrored genetic disruption this protein. Using AlphaFold2, found structurally resembles ceramide synthase acid elongase families coenzyme A-dependent lipid processing enzymes. This structural similarity included conservation catalytic histidine residues, mutation which blocked stereoprobe remodeling activity TLCD1. Taken together, data indicate acts as acyltransferase function inhibitors enzymatic activity. Our findings thus illuminate how analysis can facilitate functional annotation inhibition key metabolic enzyme cells.

Язык: Английский

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Sulfinyl Aziridines as Stereoselective Covalent Destabilizing Degraders of the Oncogenic Transcription Factor MYC

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

Опубликована: Фев. 27, 2025

While MYC is a significant oncogenic transcription factor driver of cancer, directly targeting has remained challenging due to its intrinsic disorder and poorly defined structure, deeming it "undruggable." Whether transient pockets formed within intrinsically disordered unstructured regions proteins can be selectively targeted with small molecules remains an outstanding challenge. Here, we developed bespoke stereochemically-paired spirocyclic oxindole aziridine covalent library screened this for degradation MYC. Through screen, identified hit ligand KL2-236, bearing unique sulfinyl warhead, that engaged in vitro as pure MYC/MAX protein complex situ cancer cells destabilize MYC, inhibit transcriptional activity degrade proteasome-dependent manner through C203 D205 residues. Notably, reactivity was most pronounced specific stereoisomers KL2-236 diastereomer KL4-019 largely inactive. Mutagenesis both completely attenuated KL2-236-mediated degradation. We have also optimized our initial compound generate more durable degrader KL4-219A cells. Our results reveal novel ligandable site indicate certain high-value targets, such interrogated by isomerically chiral molecules, leading destabilization

Язык: Английский

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Unraveling the nexus: Genomic instability and metabolism in cancer

Cell Reports, Год журнала: 2025, Номер 44(4), С. 115540 - 115540

Опубликована: Апрель 1, 2025

The DNA-damage response (DDR) is a signaling network that enables cells to detect and repair genomic damage. Over the past three decades, inhibiting DDR has proven be an effective cancer therapeutic strategy. Although drugs targeting have received approval for treating various cancers, tumor often develop resistance these therapies, owing their ability undergo energetic metabolic reprogramming. Metabolic intermediates also influence cells' sense oxidative stress, leading impaired redox metabolism, thus creating vulnerabilities. In this review, we summarize recent advances in understanding crosstalk between metabolism. We discuss combination therapies target DDR, vulnerabilities cancer. outline potential obstacles metabolism propose strategies overcome challenges.

Язык: Английский

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Functionalizing tandem mass tags for streamlining click-based quantitative chemoproteomics

Communications Chemistry, Год журнала: 2024, Номер 7(1)

Опубликована: Апрель 10, 2024

Abstract Mapping the ligandability or potential druggability of all proteins in human proteome is a central goal mass spectrometry-based covalent chemoproteomics. Achieving this ambitious objective requires high throughput and coverage sample preparation liquid chromatography-tandem spectrometry analysis for hundreds to thousands reactive compounds chemical probes. Conducting chemoproteomic screens at scale benefits from technical innovations that achieve increased throughput. Here we realize vision by establishing silane-based cleavable linkers isotopically-labeled proteomics-tandem tag (sCIP-TMT) proteomic platform, which distinguished early pooling increases sCIP-TMT pairs custom click-compatible sCIP capture reagent readily functionalized yield with commercially available TMT reagents. Synthesis benchmarking 10-plex set reveal substantial decrease time together accuracy quantification. By screening focused four cysteine-reactive electrophiles, demonstrate utility target hunting, identifying 789 total liganded cysteines. Distinguished its compatibility established enrichment quantification protocols, expect will translate wide range applications.

Язык: Английский

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Identification of actionable targeted protein degradation effector sites through Site-specific Ligand Incorporation-induced Proximity (SLIP)

Опубликована: Фев. 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.

Язык: Английский

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