Antibody-drug conjugates for targeted cancer therapy: recent advances in potential payloads

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 276, P. 116709 - 116709

Published: July 25, 2024

Language: Английский

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The medicinal chemistry evolution of antibody–drug conjugates

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 15(3), P. 809 - 831

Published: Jan. 1, 2024

Antibody-drug conjugates (ADCs) comprise 3 components of wildly differing sizes: antibody (150 000 Da), linker (typically <500 Da) and payload Da). While the drug-linker makes up only a small percent ADC it has disproportionately massive impact on all aspects ADC. Replacing maleimide with bromoacetamide (BrAc) affords stable attachment to cysteine, supports total flexibility for design more homogenous Optimisation protease cleavable dipeptide reduces aggregation, facilitates moderation physicochemical properties enables long-term stability facilitate subcutaneous self-administration. Payloads are designed specifically afford optimal Structural information SAR guide improve both potency selectivity molecule target improving therapeutic index resulting ADCs. Minimising solvent exposed hydrophobic surface area improves drug-like ADC, realisation that heteroatom can be than just site as also drive adoption prodrug strategy at project initiation key areas medicinal chemistry drives. For an symbiotic relationship three structurally disparate requires they function in unison huge role ensure this happens.

Language: Английский

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The New Frontier: Merging Molecular Glue Degrader and Antibody–Drug Conjugate Modalities To Overcome Strategic Challenges

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(18), P. 15996 - 16001

Published: Sept. 4, 2024

Herein, we discuss advancements in the field of a unique class antibody-drug conjugates (ADCs) named molecular glue-antibody conjugate (MAC). ADCs traditionally employ cytotoxic agents as payloads, and this approach has been used all approved to treat cancer. Complementary approach, proteolysis targeting chimera (PROTAC) degrader antibody (DACs) provide opportunity deliver these bifunctional tumors by using antibodies delivery mechanism overcome bioavailability issues encountered PROTAC payloads. Recently, cereblon binding monovalent called glues new that have coined term molecular-glue (MACs). In article, intend review made targeted cereblon-based glue degraders.

Language: Английский

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Cancer-targeting drug conjugates drives a new era in precise cancer treatment

Chinese Chemical Letters, Journal Year: 2025, Volume and Issue: unknown, P. 110960 - 110960

Published: Feb. 1, 2025

Language: Английский

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Fluorogenic Platform for Real-Time Imaging of Subcellular Payload Release in Antibody–Drug Conjugates

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: 147(9), P. 7578 - 7587

Published: Feb. 18, 2025

Antibody-drug conjugates (ADCs) represent promising therapeutic constructs to enhance the selective delivery of drugs target cells; however, attaining precise control over timing and location payload release remains challenging due complex intracellular processes that define ADC internalization, trafficking, linker cleavage. In this study, we present novel real-time fluorogenic probes monitor both subcellular dynamics trafficking release. We optimized a tandem molecular design sequential pH- enzyme-activatable naphthalimide fluorophores (1) track their localization along endolysosomal pathway (2) cleavage with OFF-to-ON fluorescence switches. Live-cell imaging microscopy revealed ADCs can traffic lysosomes yet require residence time in these compartments for efficient Notably, compact size naphthalimides did not impair recognition cell surface reporters or kinetics This modular platform is applicable many holds promise inform rational optimal profiles efficacy.

Language: Английский

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Targeting site-specific N-glycosylated B7H3 induces potent antitumor immunity

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 14, 2025

B7H3, an immune checkpoint molecule, is a highly N-glycosylated membrane protein. However, the key glycosylated asparagine residues that mediate function of B7H3 protein are still unclear. Here we identify N-glycans attached to N91/309 and N104/322 required for proper localization on cell surface membrane. We demonstrate mutations in these two pairs N-glycosylation sites induce ER accumulation by blocking its ER-to-Golgi translocation subsequently promote degradation via endoplasmic reticulum-associated pathway. Additional evidence suggests at essential inhibition T-cell proliferation activation. More importantly, monoclonal antibody, Ab-82, preferentially targeting developed, which exhibits ability elicit cytotoxic T lymphocyte-mediated antitumor immunity internalization. Together, findings offer rationale as potential strategy immunotherapy.

Language: Английский

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Ghrelin/GHSR system attenuates collagen-induced arthritis in mice and ameliorates inflammation in human rheumatoid arthritis fibroblast-like synoviocytes

Biochemical Pharmacology, Journal Year: 2025, Volume and Issue: 238, P. 116973 - 116973

Published: May 6, 2025

Language: Английский

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Therapeutic potential of isoniazid carbohydrazide derivatives as a promising anti-inflammatory and anti-diabetic drug via synthesis, characterization, biological screening, and computational studies

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: unknown, P. 141106 - 141106

Published: Dec. 1, 2024

Language: Английский

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Antibody drug conjugate combats inflammation

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(5), P. 340 - 340

Published: April 4, 2024

Language: Английский

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From ADC to XDC: Opportunities and challenges for AI in revolutionizing drug conjugate development

The Innovation Medicine, Journal Year: 2024, Volume and Issue: unknown, P. 100107 - 100107

Published: Dec. 18, 2024

Language: Английский

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