Negative Immune Checkpoint Inhibitors DOI Creative Commons
Magda Drewniak‐Świtalska, Paulina Fortuna, Małgorzata Krzystek−Korpacka

и другие.

Pharmaceutics, Год журнала: 2025, Номер 17(6), С. 713 - 713

Опубликована: Май 28, 2025

Checkpoint inhibitors are a modern therapeutic approach for treating various types of cancer, metabolic diseases, and chronic infections. The main goal this therapy is to specifically unlock the immune system, allowing it recognize eliminate cancer cells or pathogens, primarily through activation T lymphocytes. Monoclonal antibodies used in treatment cancers, such as pembrolizumab (Keytruda), nivolumab (Opdivo), ipilimumab (Yervoy), carry several limitations, due their large molecular size. challenges include limited tissue penetration, long half-life body, risk autoimmune responses. Compared antibodies, small-molecule peptide offer significant advantages related structure. These drugs demonstrate better ability penetrate hard-to-reach areas, tumor microenvironments, can be administered orally, often show lower immunogenicity. A new generation PROTACs, which combine direct proteins degradation with action checkpoint inhibitors, contributing elimination responsible suppressing response. This publication describes PROTAC molecules targeting negative checkpoints—CTLA-4, PD-1, VISTA, TIM-3, BTLA-4, LAG-3, TIGIT.

Язык: Английский

Targeting STAT3 for Cancer Therapy: Focusing on Y705, S727, or Dual Inhibition? DOI Open Access

Kyli Berkley,

Julian Zalejski, Ashutosh Sharma

и другие.

Cancers, Год журнала: 2025, Номер 17(5), С. 755 - 755

Опубликована: Фев. 23, 2025

Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that strongly implicated in various cancers. In its canonical signaling pathway, Janus kinases (JAKs) phosphorylate STAT3 at the Y705 residue response to cytokines or growth factors, with pY705 serving as key marker oncogenic activity. Elevated levels correlate poor prognosis, numerous small-molecule inhibitors have been developed block this phosphorylation site. More recently, S727 (pS727) has emerged critical contributor STAT3-mediated oncogenesis, particularly due role mitochondrial translocation. Evidence suggests pS727 may even surpass driving These findings prompt an important question: Which should be prioritized for effective inhibition cancer therapy? This review compiles critically analyzes current literature on targeting and/or pS727, evaluating their therapeutic efficacy vitro, vivo, clinical trials. We assess unique effects each downstream signaling, toxicity, outcomes. Our analysis indicates both achieve greatest effectiveness. However, associated higher toxicity risks. Comprehensive evaluation underscores importance maximum benefit. The also shows co-targeting increase overall efficacy. approached lower affinity minimize enhance feasibility dual-targeting strategies.

Язык: Английский

Процитировано

1
A Comprehensive Primer and Review of PROTACs and Their In Silico Design DOI Creative Commons

Jacopo Zattoni,

Paola Vottero,

Gea Carena

и другие.

Computer Methods and Programs in Biomedicine, Год журнала: 2025, Номер 264, С. 108687 - 108687

Опубликована: Фев. 27, 2025

Язык: Английский

Процитировано

0
A PDE4 shortform degrader: a first in isoform‐specific PDE4 inhibition DOI Creative Commons
Donald H. Maurice

FEBS Journal, Год журнала: 2025, Номер unknown

Опубликована: Март 7, 2025

Although phosphodiesterase 4 (PDE4) inhibitors have reached the clinic, their lack of selectivity for PDE4 enzyme isoforms leads to documented side effects. Building in has proved difficult because all enzymes share highly conserved catalytic domains. The report by Sin et al. describes a novel approach which potent proteolysis targeting chimera (PROTAC) selectively promotes degradation small subset (i.e., "short forms") and impacts inflammatory events regulated these enzymes. This offers unparalleled selectivity, potency, could represent dawn new pharmacology selective regulation cyclic AMP (cAMP) signaling.

Язык: Английский

Процитировано

0
Targeted Protein Degradation by KLHDC2 Ligands Identified by High Throughput Screening DOI Open Access
Han Zhou,

Tong-liang Zhou,

Wenli Yu

и другие.

Опубликована: Май 9, 2025

Abstract Proteolysis targeting chimeras (PROTACs) enable the selective and sub-stoichiometric elimination of pathological proteins, yet only two E3 ligases are routinely used for this purpose. Here, we expand repertoire PROTAC compatible by identifying a novel small molecule scaffold ubiquitin ligase KLHDC2 using fluorescence polarization-based high throughput screen. We highlight utility ligand with synthesis PROTACs capable potently degrading BRD4 in cells. This work affords additional chemical matter suggests practical approach binders screening.

Язык: Английский

Процитировано

0
Targeted Protein Degradation by KLHDC2 Ligands Identified by High Throughput Screening DOI Open Access
Han Zhou,

Tong-liang Zhou,

Wenli Yu

и другие.

Опубликована: Май 9, 2025

Abstract Proteolysis targeting chimeras (PROTACs) enable the selective and sub-stoichiometric elimination of pathological proteins, yet only two E3 ligases are routinely used for this purpose. Here, we expand repertoire PROTAC compatible by identifying a novel small molecule scaffold ubiquitin ligase KLHDC2 using fluorescence polarization-based high throughput screen. We highlight utility ligand with synthesis PROTACs capable potently degrading BRD4 in cells. This work affords additional chemical matter suggests practical approach binders screening.

Язык: Английский

Процитировано

0
Negative Immune Checkpoint Inhibitors DOI Creative Commons
Magda Drewniak‐Świtalska, Paulina Fortuna, Małgorzata Krzystek−Korpacka

и другие.

Pharmaceutics, Год журнала: 2025, Номер 17(6), С. 713 - 713

Опубликована: Май 28, 2025

Checkpoint inhibitors are a modern therapeutic approach for treating various types of cancer, metabolic diseases, and chronic infections. The main goal this therapy is to specifically unlock the immune system, allowing it recognize eliminate cancer cells or pathogens, primarily through activation T lymphocytes. Monoclonal antibodies used in treatment cancers, such as pembrolizumab (Keytruda), nivolumab (Opdivo), ipilimumab (Yervoy), carry several limitations, due their large molecular size. challenges include limited tissue penetration, long half-life body, risk autoimmune responses. Compared antibodies, small-molecule peptide offer significant advantages related structure. These drugs demonstrate better ability penetrate hard-to-reach areas, tumor microenvironments, can be administered orally, often show lower immunogenicity. A new generation PROTACs, which combine direct proteins degradation with action checkpoint inhibitors, contributing elimination responsible suppressing response. This publication describes PROTAC molecules targeting negative checkpoints—CTLA-4, PD-1, VISTA, TIM-3, BTLA-4, LAG-3, TIGIT.

Язык: Английский

Процитировано

0