New therapies on the horizon: Targeted protein degradation in neuroscience

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(9), P. 1688 - 1698

Published: Sept. 1, 2024

Language: Английский

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Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα)

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 25, 2024

Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment ER-positive (ER+) breast cancers, but new strategies are urgently needed to overcome clinical resistance. In present study, we describe discovery and extensive evaluation ERD-12310A as exceptionally potent orally efficacious PROTAC degrader ERα. achieved a DC

Language: Английский

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Stability Evaluation and Pharmacokinetic Profiling of Vepdegestrant in Rodents Using Liquid Chromatography–Tandem Mass Spectrometry

Molecules, Journal Year: 2024, Volume and Issue: 29(17), P. 4048 - 4048

Published: Aug. 27, 2024

Vepdegestrant (formerly ARV-471), a novel proteolysis-targeting chimera (PROTAC), targets estrogen receptor alpha (ERα) for degradation, offering promising option to treat advanced ER-positive breast cancer. We developed and validated sensitive rapid liquid chromatography-tandem mass spectrometry method quantify vepdegestrant in rodent plasma using bavdegalutamide ARV-110) as an internal standard. Plasma samples were prepared with protein precipitation acetonitrile analyzed reverse-phase C18 columns mobile phase of 10 mM ammonium formate distilled water acetonitrile. The demonstrated linearity from 1 1000 ng/mL mouse rat plasma, meeting all validation criteria, successfully applied vivo vitro studies. Pharmacokinetic analysis revealed low-to-moderate clearance (313.3, 1053 mL/h/kg) oral bioavailability (17.91, 24.12%) mice rats, respectively. It was unstable buffer solutions across pH 2-10 phosphate-buffered saline (pH 7.4), likely due adsorption, but remained stable at varying temperatures. In liver microsomes, exhibited moderate stability rats mice, dogs, humans. These findings enhance the understanding pharmacokinetic properties supporting further development PROTAC drugs.

Language: Английский

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Impact of Molecular Profiling on Therapy Management in Breast Cancer

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(17), P. 4995 - 4995

Published: Aug. 23, 2024

Breast cancer (BC) remains the most prevalent among women and leading cause of cancer-related mortality worldwide. The heterogeneity BC in terms histopathological features, genetic polymorphisms, response to therapies necessitates a personalized approach treatment. This review focuses on impact molecular profiling therapy management breast cancer, emphasizing recent advancements next-generation sequencing (NGS) liquid biopsies. These technologies enable identification specific subtypes detection blood-based biomarkers such as circulating tumor cells (CTCs), DNA (ctDNA), tumor-educated platelets (TEPs). integration with traditional clinical pathological data allows for more tailored effective treatment strategies, improving patient outcomes. also discusses current challenges prospects implementing therapy, highlighting potential revolutionize through precise prognostic therapeutic interventions.

Language: Английский

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Property-based optimisation of PROTACs

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

PROTACs are an emerging therapeutic approach towards targeted protein degradation. This article examines the leading examples of this modality that in clinical development through prism their physicochemical properties.

Language: Английский

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