VERITAC-2: a Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer

Future Oncology, Journal Year: 2024, Volume and Issue: 20(32), P. 2447 - 2455

Published: July 29, 2024

Vepdegestrant (ARV-471) is an oral PROTAC ER degrader that binds E3 ubiquitin ligase and to directly trigger ubiquitination of its subsequent proteasomal degradation. In a first-in-human Phase I/II study, vepdegestrant monotherapy was well tolerated with clinical activity in pretreated patients ER+/HER2- advanced breast cancer. The global, randomized III VERITAC-2 study compares efficacy safety versus fulvestrant adults cancer after treatment CDK4/6 inhibitor plus endocrine therapy. Progression-free survival by blinded independent central review (primary end point) will be assessed the intention-to-treat population ESR1 mutation-positive subpopulation. Secondary points include overall survival, tumor response, safety, pharmacokinetics, patient-reported outcomes, circulating DNA biomarkers.

Language: Английский

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CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety

Cancer Cell, Journal Year: 2025, Volume and Issue: 43(3), P. 464 - 481.e14

Published: March 1, 2025

Highlights•Atirmociclib (PF-07220060) is a next-generation CDK4 selective inhibitor•Impact reduction on neutrophils was in proportion to increase selectivity•Greater target coverage results deeper anti-tumor responses•Combinatorial agents further atirmociclib efficacySummaryCDK4/6 inhibitors have revolutionized treatment of hormone receptor positive (HR+), HER2 non-amplified (HER2−) breast cancer. Yet, all "dual" CDK4/6 show common dose-limiting hematologic toxicities, foremost neutropenia. This poses challenges provide these at concentrations necessary extinguish cell cycling tumors. HR+ cancer cells are highly dependent but not CDK6. By contrast, dispensable for human bone marrow derived cells, due the primary and compensatory role CDK6 hematopoiesis. prompted us develop (PF-07220060), inhibitor. Atirmociclib's impact circulating reduced, with its versus selectivity. Realized dose intensification led greater inhibition responses, pointing as limiting factor inhibitor efficacy. We also highlight combinatorial that may counter acquired resistance widen clinical application.Graphical abstract

Language: Английский

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The sequence–structure–function relationship of intrinsic ERα disorder

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

The oestrogen receptor (ER or ERα), a nuclear hormone that drives most breast cancer1, is commonly activated by phosphorylation at serine 118 within its intrinsically disordered N-terminal transactivation domain2,3. Although this modification enables oestrogen-independent ER function, mechanism has remained unclear despite ongoing clinical trials of kinase inhibitors targeting region4–6. By integration small-angle X-ray scattering and magnetic resonance spectroscopy with functional studies, we show triggers an unexpected expansion the domain disrupts specific hydrophobic clustering between two aromatic-rich regions. Mutations mimicking disruption rescue transcriptional activity, target-gene expression cell growth impaired phosphorylation-deficient S118A mutation. These findings, driven interactions, extend beyond electrostatic models provide mechanistic insights into proteins7, implications for other receptors8. This fundamental sequence–structure–function relationship advances our understanding intrinsic disorder, crucial developing targeted cancer therapeutics. Serine conformational changes through interactions clusters, showing how mutations can restore receptor-mediated transcription.

Language: Английский

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Single Dose of a Small Molecule Leads to Complete Regressions of Large Breast Tumors in Mice

ACS Central Science, Journal Year: 2025, Volume and Issue: 11(2), P. 228 - 238

Published: Jan. 22, 2025

Patients with estrogen receptor α positive (ERα+) breast cancer typically undergo surgical resection, followed by 5–10 years of treatment adjuvant endocrine therapy. This prolonged intervention is associated a host undesired side effects that reduce patient compliance, and ultimately therapeutic resistance disease relapse/progression are common. An ideal anticancer therapy would be effective against recurrent refractory minimal dosing; however, there little precedent for marked tumor regression single dose small molecule therapeutic. Herein we report ErSO-TFPy as induces quantitative or near-quantitative tumors in multiple mouse models dose. Importantly, this effect robust independent size eradication even very large (500−1500 mm3) observed. Mechanistically, these regressions consequence rapid induction necrotic cell death the immune independent. If successfully translated to human patients, benefits such an drug significant.

Language: Английский

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An update on promising and emerging protein kinase B/AKT inhibitors for breast cancer

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

Published: Jan. 23, 2025

Introduction . The PI3K pathway is crucial in breast cancer (BC), influencing cell survival, growth, and metabolism, with AKT playing a central role treatment resistance. This pathway's involvement carcinogenesis its link to resistance underscores the significance of targeting it BC therapy. PI3K-pathway inhibitors offer new therapeutic avenues but bring challenges, especially due toxicity issues that hinder their development.

Language: Английский

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Discovery of D-Ring-Contracted Artemisinin as a Potent Hydrophobic Tag for Targeted Protein Degradation

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

The relentless pursuit of innovative hydrophobic tags remains a formidable challenge within the realm targeted protein degradation. Herein, we have uncovered remarkable potential D-ring-contracted artemisinin as potent tag that demonstrates exceptional degradation efficiency. We crafted series conjugates by fusing with raloxifene, and among these,

Language: Английский

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Liquid Chromatography Combined With Tandem Mass Spectrometry for the Pharmacokinetic and Metabolism Studies of PROTAC ARV‐471 in Rats

Biomedical Chromatography, Journal Year: 2025, Volume and Issue: 39(2)

Published: Jan. 2, 2025

Proteolysis targeting chimera (PROTAC) is emerging as a promising medicinal modality, which has aroused widespread interest among the field of pharmaceutical manufacturing in recent years. ARV-471 an orally active PROTAC estrogen receptor degrader against breast cancer, leads to ubiquitylation and subsequent degradation receptors via proteasome. In this study, we developed highly sensitive liquid chromatography tandem mass spectrometry method (LLOQ = 0.5 ng/mL) for measurement rat plasma. The acetonitrile precipitated sample was separated on ACQUITY BEH C

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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Efficient Stereoselective Synthesis of Vepdegestrant (ARV‐471) via Ruthenium‐Catalyzed Asymmetric Hydrogenation

ChemistrySelect, Journal Year: 2025, Volume and Issue: 10(4)

Published: Jan. 1, 2025

Abstract Vepdegestrant (ARV‐471) is a novel estrogen receptor (ER) degrader currently under clinical evaluation for the treatment of ER‐positive and HER2‐negative breast cancer. We have developed an efficient catalytic stereoselective synthetic route to produce this important compound. The key step involves Ruthenium‐catalyzed asymmetric hydrogenation, which establishes critical stereocenter with exceptional diastereoselectivity(>99% de). This method obviates need chiral chromatographic separation, thereby significantly improving efficiency scalability sequence compared previously reported approaches.

Language: Английский

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PROTACs coupled with oligonucleotides to tackle the undruggable

Bioanalysis, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 16

Published: Feb. 3, 2025

Undruggable targets account for roughly 85% of human disease-related and represent a category therapeutic that are difficult to tackle with traditional methods, but their considerable clinical importance. These generally defined by planar functional interfaces the absence efficient ligand-binding pockets, making them unattainable conventional pharmaceutical strategies. The advent oligonucleotide-based proteolysis-targeting chimeras (PROTACs) has instilled renewed optimism in addressing these challenges. PROTACs facilitate targeted degradation undruggable entities, including transcription factors (TFs) RNA-binding proteins (RBPs), via proteasome-dependent mechanisms, thereby presenting novel approaches diseases linked targets. This review offers an in-depth examination recent progress integration PROTAC technology oligonucleotides target traditionally proteins, emphasizing design principles mechanisms action innovative PROTACs.

Language: Английский

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