Targeted Covalent Modification Strategies for Drugging the Undruggable Targets

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

Published: Jan. 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.

Language: Английский

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Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders

Cells, Journal Year: 2024, Volume and Issue: 13(7), P. 578 - 578

Published: March 26, 2024

Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding ubiquitin ligase. More generally referred as bifunctional degraders, PROTACs have led the way in field targeted protein (TPD), with several currently undergoing clinical testing. Alongside single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered viable approach for development therapeutics, driven advances rational discovery approaches. This review focuses on drug respect within proteasome system, including analysis mechanistic concepts approaches, an overview current pre-clinical degrader status oncology, neurodegenerative inflammatory disease.

Language: Английский

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Unleashing the Power of Covalent Drugs for Protein Degradation

Medicinal Research Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

ABSTRACT Targeted protein degradation (TPD) has emerged as a significant therapeutic approach for variety of diseases, including cancer. Advances in TPD techniques, such molecular glue (MG) and lysosome‐dependent strategies, have shown substantial progress since the inception first PROTAC 2001. The methodology represents forefront technology, with ongoing evaluation more than 20 clinical trials treatment diverse medical conditions. Two prominent PROTACs, ARV‐471 ARV‐110, are currently undergoing phase III II trials, respectively. Traditional PROTACs encountering obstacles limited binding affinity restricted range E3 ligase ligands facilitating interest (POI) degradation. Covalent medicines offer potential to enhance efficacy by enabling targeting previously considered “undruggable” shallow sites. Strategic alterations allow establish covalent connections particular target proteins, Kirsten rat sarcoma viral oncogene homolog (KRAS), Bruton's tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), well ligases DDB1 CUL4 associated 16 (DCAF16) Kelch‐like ECH‐associated 1 (Keap1). concept also been utilized various new forms degraders, molecule (MG), in‐cell click‐formed proteolysis chimera (CLIPTAC), HaloPROTAC, lysosome‐targeting (LYTAC) GlueTAC. This review focuses on recent advancements degraders beyond examines future directions pertinent this field.

Language: Английский

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Total syntheses of cyclohelminthol I–IV reveal a new cysteine-selective covalent reactive group

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

Published: Jan. 1, 2025

Biocompatible covalent reactive groups (CRGs) play pivotal roles in several areas of chemical biology and the life sciences, including targeted inhibitor design preparation advanced biologic drugs, such as antibody-drug conjugates. In this study, we present discovery that small, chlorinated polyketide natural product cyclohelminthiol II (CHM-II) acts a new type cysteine/thiol-targeting CRG incorporating both reversible irreversible reactivity. We devise first syntheses four simple cyclohelminthols, (±)-cyclohelminthol I-IV, with selective chlorinations (at C2 C5) Ni-catalyzed reductive cross coupling between an enone, vinyl bromide triethylsilyl chloride key steps. Unbiased biological profiling (cell painting) was used to discover putative mechanism for CHM-II cells subsequent validation experiments demonstrating mechanistic similarity dimethyl fumarate (DMF) - known (covalent) drug treatment multiple sclerosis. Focused biochemical revealed divergent thiol-reactivity inherent scaffold through further derivatization applied activity-based protein (ABPP)-workflows show exclusive cysteine-labelling cell lysate. Overall, study provides efficient synthetic access chemotype neighboring space proof-of-concept potential applications privileged CRG-class within biology.

Language: Английский

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

Published: Feb. 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.

Language: Английский

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Challenges, opportunities and therapeutic potential of JAK inhibitors and their derived PROTACs (2022 – 2023)

Expert Opinion on Therapeutic Patents, Journal Year: 2025, Volume and Issue: unknown

Published: March 8, 2025

Introduction Since the approval of first JAK inhibitor, ruxolitinib, in 2011, development inhibitors has expanded significantly, with applications spanning autoimmune diseases, cancer, and inflammatory disorders. This review explores challenges therapeutic potential their evolution into proteolysis-targeting chimeras (PROTACs), which offer novel avenues for selective modulation.

Language: Английский

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Discovery and optimisation of a covalent ligand for TRIM25 and its application to targeted protein ubiquitination

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

Published: Jan. 1, 2025

Covalent fragment screening coupled with ‘direct-to-biology’ optimisation has identified covalent binders of TRIM25 PRYSPRY, expanding the repertoire liganded E3 ligases and providing new avenues for targeted protein ubiquitination.

Language: 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, Journal Year: 2025, Volume and Issue: 16(4), P. 693 - 699

Published: March 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.

Language: Английский

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Covalent Proximity Inducers

Chemical Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 18, 2024

Molecules that are able to induce proximity between two proteins finding ever increasing applications in chemical biology and drug discovery. The ability introduce an electrophile make such inducers covalent can offer improved properties as selectivity, potency, duration of action, reduced molecular size. This concept has been heavily explored the context targeted degradation particular for bivalent molecules, but recently, additional reported other contexts, well monovalent glues. is a comprehensive review inducers, aiming identify common trends current gaps their discovery application.

Language: Английский

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Application of covalent modality in proximity-induced drug pharmacology: Early development, current strategy, and feature directions

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 271, P. 116394 - 116394

Published: April 17, 2024

Language: Английский

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