Expanding the ligand spaces for E3 ligases for the design of protein degraders

Bioorganic & Medicinal Chemistry, Год журнала: 2024, Номер 105, С. 117718 - 117718

Опубликована: Апрель 12, 2024

Targeted protein degradation (TPD) has recently emerged as an exciting new drug modality. However, the strategy of developing small molecule-based degraders evolved over past two decades and now established molecular tags that are already in clinical use, well chimeric molecules, PROteolysis TArgeting Chimeras (PROTACs), based mainly on ligand systems developed for E3 ligases CRBN VHL. The large size human ligase family suggests PROTACs can be by targeting a diversity ligases, some which have restricted expression patterns with potential to design disease- or tissue-specific degraders. Indeed, many ligands been published recently, confirming druggability ligases. This review summarises recent data highlights challenges these molecules into efficient rivalling degrader systems.

Язык: Английский

---

Pharmacotherapeutic strategies for Friedreich Ataxia: a review of the available data

Expert Opinion on Pharmacotherapy, Год журнала: 2024, Номер 25(5), С. 529 - 539

Опубликована: Март 23, 2024

Friedreich ataxia (FRDA) is a rare autosomal recessive disease, marked by loss of coordination as well impaired neurological, endocrine, orthopedic, and cardiac function. There are many symptomatic medications for FRDA, clinical trials have been performed, but only one FDA-approved medication exists.

Язык: Английский

---

Emodin, a Potent Anthraquinone Mitigates MPTP-Induced Parkinsons’ Disease Pathology by Regulating Nrf2 and Its Downstream Targets: In Silico and In Vivo Approach

Molecular Neurobiology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

Язык: Английский

---

Design, synthesis and biological evaluation of glucose metabolism inhibitors as anticancer agents

Bioorganic Chemistry, Год журнала: 2024, Номер 151, С. 107665 - 107665

Опубликована: Июль 26, 2024

Compared to normal cells, tumour cells exhibit an upregulation of glucose transporters and increased rate glycolytic activity. In previous research, we successfully identified a promising hit compound BH10 through rigorous screening process, which demonstrates potent capacity for inhibiting cancer cell proliferation by targeting metabolism. the current study, identify Kelch-like ECH-associated protein 1 (Keap1) as potential target via avidin pull-down assays with biotinylated-BH10. Subsequently, present comprehensive analysis series analogues characterized incorporation naphthoimidazole scaffold introduction triazole ring diverse terminal functional groups. Notably, 4d has emerged most candidate, exhibiting better anti-cancer activities against HEC1A IC50 2.60 μM, extended biological half-life, improved pharmacokinetic profile (compared BH10) in mice.

Язык: Английский

---

A non-bactericidal cathelicidin with antioxidant properties ameliorates UVB-induced mouse skin photoaging via intracellular ROS scavenging and Keap1/Nrf2 pathway activation

Free Radical Biology and Medicine, Год журнала: 2024, Номер 224, С. 144 - 161

Опубликована: Авг. 23, 2024

Язык: Английский

---

Patenting perspective on Keap1 inhibitors (2019-2024)

Expert Opinion on Therapeutic Patents, Год журнала: 2025, Номер unknown

Опубликована: Фев. 5, 2025

Introduction Kelch-like ECH-associated protein 1 (Keap1), an E3 ligase negatively regulating the nuclear factor erythroid 2-related 2 (Nrf2), has emerged as auspicious drug target for treating ailments associated with oxidative stress and inflammation. Discovery of Keap1 inhibitors have attracted significant interest.

Язык: Английский

---

Design and synthesis of novel cyclohexanecarboxamides with anticonvulsant effect by activating Nrf2-ARE pathway

Bioorganic Chemistry, Год журнала: 2025, Номер 159, С. 108357 - 108357

Опубликована: Март 10, 2025

Язык: Английский

---

Green procedures for synthesizing potential hNMDA receptor allosteric modulators through reduction and one-pot reductive acetylation of nitro(hetero)arenes using a superparamagnetic Fe₃O₄@APTMS@Cp₂ZrCl_{x (x = 0, 1, 2)} nanocatalyst

Nanoscale Advances, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

In this research, we have developed diverse strategies for synthesizing potential h NMDA receptor allosteric modulators through reduction and one-pot reductive acetylation of nitro(hetero)arenes using a mesoporous zirconocene-containing nanocatalyst.

Язык: Английский

---

Redox homeostasis and inflammation in fibroblasts of patients with Friedreich Ataxia: a possible cross talk

Frontiers in Molecular Neuroscience, Год журнала: 2025, Номер 18

Опубликована: Апрель 16, 2025

Redox homeostasis is impaired in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of mitochondrial protein frataxin. Nrf2, master regulator tissue redox balance, defective disease, driving cells to ferroptosis. Neuro-inflammation recently emerging as an additional pathological mechanism FRDA and has be understood order go deeper into pathogenesis disease. As functional cross talk between Nrf2 NF-kB pathways been previously reported, we wonder if inflammation may activated consequence deficiency. Thus, analyzed proteins involved antioxidant inflammatory responses fibroblasts patients with FRDA. We found significant activation TLR4/NF-kB/IL-1β axis patients, associated consistent increase enzymes thioredoxin 1 (TRX1) glutaredoxin (GLRX1), which are essential activate under oxidative stress conditions. Furthermore, investigated role 4-HNE, by-product lipid peroxidation, potential mediator ferroptosis

Язык: Английский

---

Preclinical Research on Cinnamic Acid Derivatives for the Prevention of Liver Damage: Promising Therapies for Liver Diseases

Biomedicines, Год журнала: 2025, Номер 13(5), С. 1094 - 1094

Опубликована: Апрель 30, 2025

Background: Liver diseases are a global health issue with an annual mortality of 80,000 patients, mainly due to complications that arise during disease progression, as effective treatments lacking. Objectives: This study evaluated the hepatoprotective effects two derivatives cinnamic acid, LQM717 and LQM755, in murine model acute liver damage induced by carbon tetrachloride (CCl4, 4 g/kg, single dose p.o.). Methods: Male Wistar rats were pretreated five doses (20 mg/kg i.p.) or LQM755 (equimolar dose), starting 2 days before inducing hepatotoxic CCl4. Results: The key parameters hepatocellular function showed significant increases ALT, ALP, GGT, total direct bilirubin intoxicated CCl4, decreased glycogen serum albumin. Macroscopic microscopic examinations revealed reduced inflammation, necrosis, steatosis animals LQM755. Hepatomegaly was observed only + CCl4 group. statistically provided partial protection against ALT ALP completely prevented elevations GGT bilirubin. albumin reduction, while partially it. Both compounds depletion. Bioinformatic analysis identified 32 potential protein targets for 36 Conclusions: These findings suggest have CCl4-induced injury, providing information future studies other chronic models, well elucidate their mechanisms action.

Язык: Английский

---