Agnieszka Zagórska

Triple-negative breast cancer (TNBC), particularly when associated with breast cancer susceptibility gene 1/2 (BRCA1/2) alterations or homologous recombination deficiency (HRD), remains therapeutically challenging because DNA repair vulnerabilities coexist with molecular heterogeneity, resistance, and toxicity constraints. This narrative review synthesizes mechanistic, preclinical, clinical, and translational evidence on DNA damage response (DDR)-targeted and synthetic lethality-based strategies in TNBC. We summarize TNBC biological heterogeneity, current biomarker-guided treatment options, mechanisms of poly(ADP-ribose) polymerase (PARP) inhibition and resistance, and emerging DDR targets, including ataxia telangiectasia and Rad3-related/checkpoint kinase 1 (ATR/CHK1), WEE1, DNA-dependent protein kinase (DNA-PK), RAD51, DNA polymerase theta (POLQ), neddylation-related pathways, and targeted protein degradation. The review highlights that PARP inhibitors and platinum agents provide clinically validated examples of exploiting HRD in selected populations, whereas most next-generation DDR inhibitors remain preclinical, investigational, or in early clinical trials. Resistance mechanisms, including BRCA reversion, homologous recombination restoration, replication fork stabilization, and checkpoint adaptation, limit durable benefit. Safety, target selectivity, overlapping toxicities, and the lack of standardized functional biomarkers further constrain translation. Future progress will require prospective biomarker validation, dynamic HRD assessment, rational scheduling of combinations, and medicinal chemistry approaches that improve therapeutic index rather than a broad application of DDR inhibition across all TNBC.

TAAR1 agonists have emerged as promising therapeutic agents capable of modulating glucose homeostasis, enhancing insulin secretion and suppressing appetite, making them attractive candidates for the treatment of obesity and related metabolic disorders. Despite their potential, the number of TAAR1-targeting compounds with well-defined pharmacological profiles remains limited. In this study, we identified and characterized JP-14, a novel aminoguanidine-based TAAR1 agonist, in a comprehensive panel of pharmacological assays. JP-14 promoted glucose uptake in HepG2 cells and reduced lipid deposition during 3T3-L1 adipocyte differentiation, with both actions dependent on TAAR1 signaling. In differentiated 3T3-L1 adipocytes, JP-14 reduced intracellular levels of both neutral lipids and phospholipids, indicating dual anti-steatotic and anti-phospholipidotic activity. In zebrafish larvae, toxicity profiling confirmed 10 µg/mL as a safe concentration for further in vivo studies. These assays showed that JP-14 promoted lipid mobilization and partially prevented fructose-induced lipid accumulation, demonstrating systemic metabolic benefits in vivo. Moreover, JP-14 markedly delayed gastric emptying in mice, an effect similar to loperamide and reversed by TAAR1 antagonism, supporting its role in regulating satiety and energy balance. Collectively, our findings establish JP-14 as a safe and metabolically active TAAR1 agonist with multifaceted effects on glucose and lipid metabolism. JP-14 represents a valuable pharmacological tool for probing TAAR1-mediated mechanisms in metabolic regulation.

Here, 2-(2-(Benzylamino)-2-oxoethyl)-1-methyl-1H-pyrrole-3-carboxylic acid was efficiently synthesised in good yield via an amide coupling reaction between 2-carboxymethyl-1-methyl-1H-pyrrole-3-carboxylic acid and benzylamine, employing TBTU as the coupling reagent and DIPEA as the base. The reaction was carried out in dichloromethane at room temperature. The compound was characterised by melting point determination, ¹H and ¹³C NMR, IR spectroscopy, and mass spectrometry. The combined analytical data confirm the target molecule’s successful synthesis and structural integrity.

Millions worldwide suffer from chronic pain, a complex condition often accompanied by depression and anxiety, highlighting the urgent need for innovative treatments. Classic psychedelics, including psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), primarily act on serotonin 5-HT_2A receptors and have emerged as potential modulators of pain perception and mood regulation. These substances may offer an alternative to conventional analgesics, such as opioids and nonsteroidal anti-inflammatory drugs (NSAIDs), by influencing neuroplasticity, descending pain modulation pathways, and inflammatory processes. Evidence from case studies, preclinical research, and early phase clinical trials suggests that psychedelics may alleviate pain in conditions such as cluster headaches, migraines, fibromyalgia, and chronic pain syndromes. However, the exact mechanisms underlying their analgesic properties are yet to be fully understood. While psychedelics show promise in reshaping pain management strategies, rigorous randomized controlled trials are needed to establish their safety, efficacy, and optimal dosing. This review highlights the therapeutic potential of psychedelics for chronic pain and emphasizes the necessity of further research to validate their role in modern pain medicine.

Trichomoniasis, a prevalent sexually transmitted parasitic infection caused by Trichomonas vaginalis , represents a significant public health concern with transboundary implications. In males, trichomoniasis is often asymptomatic, whereas in females, the infection is a common cause of vaginal discharge. It is connected with multiple adverse sexual and reproductive health outcomes, damaging the health of millions of humans. This review describes the current treatment of T. vaginalis infection, including metronidazole (and its mechanism of action), tinidazole, and secnidazole. Here, we highlight the challenges to managing trichomoniasis, including mild or severe side effects of the drug and/or drug resistance. Furthermore, the review focuses also on drug repurposing and current promising drug targets. To emphasize the impact of nanocarriers on drug efficacy, we consolidated the published data on the activity of various drug delivery systems such as liposomes, nanoemulsions, nanoparticles, nanocapsules, and others against T. vaginalis as well as Trichomonas gallinae and Trichomonas foetus . The present work explores the recent advances in the quest for antiprotozoal agents against trichomoniasis while delving into the challenges that persist in this endeavor.

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it a significant target for developing antiviral drugs. The inhibition of SARS-CoV-2 Mpro has emerged as a promising approach for developing therapeutic agents to treat COVID-19. This review explores the structure of the Mpro protein and analyzes the progress made in understanding protein–ligand interactions of Mpro inhibitors. It focuses on binding kinetics, origin, and the chemical structure of these inhibitors. The review provides an in-depth analysis of recent clinical trials involving covalent and non-covalent inhibitors and emerging dual inhibitors targeting SARS-CoV-2 Mpro. By integrating findings from the literature and ongoing clinical trials, this review captures the current state of research into Mpro inhibitors, offering a comprehensive understanding of challenges and directions in their future development as anti-coronavirus agents. This information provides new insights and inspiration for medicinal chemists, paving the way for developing more effective Mpro inhibitors as novel COVID-19 therapies.

New protocol for the preparation of the novel caffeic acid derivatives using the Wittig reaction has been applied to follow the principles of green chemistry. The compounds have been evaluated against chloroquine-sensitive and chloroquine-resistant P. falciparum strains. Their cytotoxicity to normal human dermal fibroblasts and their propensity to induce hemolysis have been also determined. Ethyl (2E)-3-(2,3,4-trihydroxyphenyl)-2-methylpropenoate has exhibited the highest antiplasmodial activity against P. falciparum strains without the cytotoxic and hemolytic effects. This derivative is significantly more potent than caffeic acid parent structure. The application of our one-step procedure has been shown to be rapid and efficient. It allows for an easy increase of input data to refine the structure-activity relationship model of caffeates as the antimalarials. The one-step approach meets the conditions of atom economy and eliminates hazardous materials. Water has been used as the effective medium for the Wittig reaction to avoid toxic organic solvents.

Dementia, most often associated with neurodegenerative diseases, affects millions of people worldwide, predominantly the elderly. Unfortunately, no treatment is still available. Therefore, there is an urgent need to address this situation. This review presents the state of the art of drug discovery and developments in targeting dementia. Several approaches are discussed, such as drug repurposing, the use of small molecules, and phosphodiesterase inhibitors. Furthermore, the review also provides insights into clinical trials of these molecules. Emphasis has been placed on small molecules and multi-target-directed ligands, as well as disease-modifying therapies. Finally, attention is drawn to the possibilities of applications of nanotechnology in managing dementia.