Palbociclib as an Antitumor Drug: A License to Kill DOI Creative Commons
Agnieszka Łupicka‐Słowik, Federica Cossu, Marcin Sieńczyk

и другие.

Molecules, Год журнала: 2024, Номер 29(22), С. 5334 - 5334

Опубликована: Ноя. 13, 2024

Neoplastic cells are characterized by uncontrolled cell divisions caused cycle dysregulation. Key regulatory proteins governing the transition from G1 to S phase CDK4 and CDK6 kinases, which controlled D-type cyclins. The CDK4/6 kinases enable use of these as targets for anticancer therapy because they prevent growth development malignant inhibiting their activity. This paper surveys clinical trial results concerning palbociclib, first in-class FDA-approved drug hormone-dependent breast cancer. It discusses therapeutic applications in cancer well solid tumors hematopoietic malignancies. Additionally, presents an analysis palbociclib resistance acquired during explores new approaches, such modifications that enhance its desired activity or open up possibilities (PROTACs).

Язык: Английский

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

Riccardo Asnaghi,

Gabriele Antonarelli,

Elena Battaiotto

и другие.

Expert Opinion on Pharmacotherapy, Год журнала: 2025, Номер unknown

Опубликована: Янв. 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.

Язык: Английский

Процитировано

1
Proteolytic therapeutic modalities for amyloidoses: Insights into immunotherapy, PROTAC, and photo-oxygenation DOI Creative Commons

Mai Kuriyama,

C Wang,

Takahide Nagase

и другие.

Neurotherapeutics, Год журнала: 2025, Номер unknown, С. e00548 - e00548

Опубликована: Фев. 1, 2025

Amyloidoses, which are characterized by abnormal accumulation of amyloid proteins leading to organ dysfunction, represent a major therapeutic challenge. They include neurodegenerative diseases, such as Alzheimer disease (AD), tauopathies and synucleinopathies. Since amyloids causative factors in these the importance proteolytic methods remove amyloid, immunotherapy Proteolysis Targeting Chimera (PROTAC) technology, has been recognized. Immunotherapy removes target antibody-mediated reactions is most studied method practical use for treatment AD. PROTAC small molecule that uses ubiquitin-proteasome system degrade intracellular demonstrated efficacy clinical trials other diseases. In addition, new modality called photo-oxygenation developed. Photo-oxygenation selectively adding oxygen using photocatalyst, compound activated light. Studies both vitro vivo have shown promising results inhibiting aggregation enhancing clearance proteins. this review, we introduce discuss modalities, provide insights into potential future directions application amyloidoses.

Язык: Английский

Процитировано

1
Development of a Versatile System for Evaluating the Target Protein Degradation Activity of Novel Ubiquitin Ligases Utilizing Existing PROTACs DOI
Shinya Sato,

M. Matsukawa,

Mitsuru Takemoto

и другие.

Biochemical and Biophysical Research Communications, Год журнала: 2025, Номер 749, С. 151370 - 151370

Опубликована: Янв. 20, 2025

Язык: Английский

Процитировано

0
Unleashing the Power of Covalent Drugs for Protein Degradation DOI Open Access

Meng‐Jie Fu,

Hang Jin,

Shao‐Peng Wang

и другие.

Medicinal Research Reviews, Год журнала: 2025, Номер unknown

Опубликована: Янв. 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.

Язык: Английский

Процитировано

0
Computational approaches to aid PROTAC drug discovery DOI

Sohini Chakraborti,

Kirsten McAulay

Elsevier eBooks, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Strategies to Overcome Resistance to Osimertinib in EGFR-Mutated Lung Cancer DOI Open Access
Donatella Romaniello,

Alessandra Morselli,

Ilaria Marrocco

и другие.

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(7), С. 2957 - 2957

Опубликована: Март 25, 2025

Non-small-cell lung cancer (NSCLC) represents the most common type of cancer. The majority patients with characterized by activating mutations in epidermal growth factor receptor (EGFR), benefit from therapies entailing tyrosine kinase inhibitors (TKIs). In this regard, osimertinib, a third-generation EGFR TKI, has greatly improved outcome for EGFR-mutated AURA and FLAURA trials displayed superiority TKI both first- second-line settings, making it drug choice treating Unfortunately, onset resistance is almost inevitable. On-target mechanisms include new (e.g., C797S) domain EGFR, while among off-target mechanisms, amplification MET or HER2, downstream signaling molecules, oncogenic fusions, phenotypic changes EMT) have been described. This review focuses on strategies that are currently being investigated, preclinical clinical to overcome including use fourth-generation TKIs, PROTACs, bispecific antibodies, ADCs, as monotherapy part combination therapies.

Язык: Английский

Процитировано

0
The Peptide PROTAC Modality: A New Strategy for Drug Discovery DOI Creative Commons
Youmin Zhu, Yu Dai,

Yun-Cai Tian

и другие.

MedComm, Год журнала: 2025, Номер 6(4)

Опубликована: Март 24, 2025

ABSTRACT In recent years, proteolysis targeting chimera (PROTAC) technology has made significant progress in the field of drug development. Traditional drugs mainly focus on inhibiting or activating specific proteins, while PROTAC provides new ideas for treating various diseases by inducing degradation target proteins. Especially peptide PROTACs, due to their unique structural and functional characteristics, they have become a hot research topic. This review detailed description key components, mechanisms, design principles elaborates applications skin‐related diseases, oncology, other potential therapeutic fields, analyzes advantages challenges, looks forward future development prospects. The not only opens up paths development, but also solving resistance safety issues faced traditional small‐molecule drugs. Compared with PROTACs such as multitargeting, biodegradability, low toxicity, flexibility design. With deepening continuous maturity technology, are expected one important strategies discovery, providing hope treatment more intractable diseases. Peptide ushering era precision medicine.

Язык: Английский

Процитировано

0
Identification of E3 Ubiquitin Ligase Substrates Using Biotin Ligase-Based Proximity Labeling Approaches DOI Creative Commons
Koji Matsuhisa, Shinya Sato, Masayuki Kaneko

и другие.

Biomedicines, Год журнала: 2025, Номер 13(4), С. 854 - 854

Опубликована: Апрель 2, 2025

Ubiquitylation is a post-translational modification originally identified as the first step in protein degradation by ubiquitin–proteasome system. also known to regulate many cellular processes without degrading ubiquitylated proteins. Substrate proteins are specifically recognized and ubiquitin ligases. It necessary identify substrates for each ligase understand physiological pathological roles of ubiquitylation. Recently, promiscuous mutant biotin derived from Escherichia coli, BioID, its variants have been utilized analyze protein–protein interaction. In this review, we summarize current knowledge regarding molecular mechanisms underlying ubiquitylation, BioID-based approaches interactome studies, application BirA identification substrates.

Язык: Английский

Процитировано

0
Recent advances in PROTAC-based antiviral and antibacterial therapeutics DOI
Can Zhou, Shiwei Yang, Jun Wang

и другие.

Bioorganic Chemistry, Год журнала: 2025, Номер unknown, С. 108437 - 108437

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0
Vepdegestrant for the treatment of HR+/HER2– breast cancer DOI
Toru Mukohara

Expert Opinion on Pharmacotherapy, Год журнала: 2025, Номер unknown

Опубликована: Апрель 3, 2025

The treatment of advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer has been improved through the development endocrine therapy (ET) targeted agents. However, resistance to ET, particularly caused by ESR1 mutations, not fully addressed. Vepdegestrant is a first-in-class, selective, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) estrogen (ER) degrader. Preclinical studies have suggested promising activity vepdegestrant irrespective genotypes. Phase I II clinical revealed favorable safety profile encouraging efficacy as single agent in combination with other results phase III VERITAC-2 study, comparing fulvestrant, are expected be available 2025, will provide first data on true significance vepdegestrant. Several combinations including + atirimociclib (a cyclin-dependent kinase 4 inhibitor) or planned conducted. these may only transform landscape for HR+/HER2- but pave way PROTAC new class anti-cancer drugs that make previously undruggable targets druggable.

Язык: Английский

Процитировано

0