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Cancer Discovery May 2021Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative...
Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC-regulated gene expression. In AR-SV-driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer. SIGNIFICANCE: Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies...
Topics: Androgen Receptor Antagonists; Animals; Cell Line, Tumor; Cell Proliferation; Humans; Imidazoles; Male; Mice; Oxazoles; Prostatic Neoplasms, Castration-Resistant; Xenograft Model Antitumor Assays; p300-CBP Transcription Factors
PubMed: 33431496
DOI: 10.1158/2159-8290.CD-20-0751 -
Magnesium Research Jun 2016Magnesium is an important micronutrient essential for various biological processes and its deficiency has been linked to several inflammatory disorders in humans....
Magnesium is an important micronutrient essential for various biological processes and its deficiency has been linked to several inflammatory disorders in humans. Topical magnesium delivery is one of the oldest forms of therapy for skin diseases, for example Dead Sea therapy and Epsom salt baths. Some anecdotal evidence and a few published reports have attributed amelioration of inflammatory skin conditions to the topical application of magnesium. On the other hand, transport of magnesium ions across the protective barrier of skin, the stratum corneum, is contentious. Our primary aim in this study was to estimate the extent of magnesium ion permeation through human skin and the role of hair follicles in facilitating the permeation. Upon topical application of magnesium solution, we found that magnesium penetrates through human stratum corneum and it depends on concentration and time of exposure. We also found that hair follicles make a significant contribution to magnesium penetration.
Topics: Fura-2; Hair Follicle; Humans; Ions; Magnesium; Skin
PubMed: 27624531
DOI: 10.1684/mrh.2016.0402 -
Clinical Pharmacokinetics Apr 2022Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections. The... (Review)
Review
Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections. The aim of the review was to summarize and critically review the key pharmacokinetic and pharmacodynamic aspects of tedizolid. Tedizolid displays linear pharmacokinetics with good tissue penetration. In in vitro susceptibility studies, tedizolid exhibits activity against the majority of Gram-positive bacteria (minimal inhibitory concentration [MIC] of ≤ 0.5 mg/L), is four-fold more potent than linezolid, and has the potential to treat pathogens being less susceptible to linezolid. Area under the unbound concentration-time curve (fAUC) related to MIC (fAUC/MIC) was best correlated with efficacy. In neutropenic mice, fAUC/MIC of ~ 50 and ~ 20 induced bacteriostasis in thigh and pulmonary infection models, respectively, at 24 h. The presence of granulocytes augmented its antibacterial effect. Hence, tedizolid is currently not recommended for immunocompromised patients. Clinical investigations with daily doses of 200 mg for 6 days showed non-inferiority to twice-daily dosing of linezolid 600 mg for 10 days in patients with acute bacterial skin and skin-structure infections. In addition to its use in skin and skin-structure infections, the high pulmonary penetration makes it an attractive option for respiratory infections including Mycobacterium tuberculosis. Resistance against tedizolid is rare yet effective antimicrobial surveillance and defining pharmacokinetic/pharmacodynamic targets for resistance suppression are needed to guide dosing strategies to suppress resistance development.
Topics: Animals; Anti-Bacterial Agents; Humans; Mice; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Oxazolidinones; Tetrazoles
PubMed: 35128625
DOI: 10.1007/s40262-021-01099-7 -
Angewandte Chemie (International Ed. in... Jun 2016Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades... (Review)
Review
Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last-resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled "Combat drug resistance: no action today means no cure tomorrow" triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Drug Design; Drug Resistance, Multiple, Bacterial; Macrolides; Molecular Dynamics Simulation; Organophosphates; Oxazoles; Oxazolidinones; Structure-Activity Relationship
PubMed: 27000559
DOI: 10.1002/anie.201506818 -
Biomedicine & Pharmacotherapy =... Jun 2021Thiazole and oxazole are compounds with a heterocyclic nucleus that have attracted the attention of medicinal chemistry due to the great variety of biological activities... (Review)
Review
Thiazole and oxazole are compounds with a heterocyclic nucleus that have attracted the attention of medicinal chemistry due to the great variety of biological activities that they enable. In recent years, their study has increased, finding a wide range of biological activities, including antifungal, antiparasitic, anti-inflammatory, and anticancer activities. This systematic review provides evidence from the literature on the antiproliferative and antitumor activities of thiazole and oxazole and their derivatives from 2014 to April 2020. Three bibliographical databases were consulted (PubMed, Web of Science, and Scopus), and a total of 32 studies were included in this paper based on our eligibility criteria. The analysis of the activity-structure relationship allows us to conclude that most of the promising compounds identified contained thiazole nuclei or derivatives.
Topics: A549 Cells; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antifungal Agents; Cell Proliferation; HeLa Cells; Hep G2 Cells; Humans; Oxazoles; Structure-Activity Relationship; Thiazoles
PubMed: 33765586
DOI: 10.1016/j.biopha.2021.111495 -
Cold Spring Harbor Perspectives in... Jan 2015Tuberculosis is an airborne infectious disease treated with combination therapeutic regimens. Adherence to long-term antituberculosis therapy is crucial for maintaining... (Review)
Review
Tuberculosis is an airborne infectious disease treated with combination therapeutic regimens. Adherence to long-term antituberculosis therapy is crucial for maintaining adequate blood drug level. The emergence and spread of drug-resistant Mycobacterium tuberculosis strains are mainly favored by the inadequate medical management of the patients. The therapeutic approach for drug-resistant tuberculosis is cumbersome, because of the poor, expensive, less-effective, and toxic alternatives to the first-line drugs. New antituberculosis drugs (bedaquiline and delamanid) have been recently approved by the health authorities, but they cannot represent the definitive solution to the clinical management of drug-resistant tuberculosis forms, particularly in intermediate economy settings where the prevalence of drug resistance is high (China, India, and former Soviet Union countries). New research and development activities are urgently needed. Public health policies are required to preserve the new and old therapeutic options.
Topics: Antitubercular Agents; China; Diarylquinolines; Humans; India; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; USSR
PubMed: 25573773
DOI: 10.1101/cshperspect.a017822 -
Marine Drugs Apr 2020Oxazole-containing peptides are mostly of marine origin and they form an intriguing family with a broad range of biological activities. Here we classify these peptides... (Review)
Review
Oxazole-containing peptides are mostly of marine origin and they form an intriguing family with a broad range of biological activities. Here we classify these peptides on the basis of their chemical structure and discuss a number of representatives of each class that reflect the extraordinary potential of this family as a source of new drugs.
Topics: Animals; Aquatic Organisms; Drugs, Investigational; Oxazoles
PubMed: 32290087
DOI: 10.3390/md18040203 -
Molecules (Basel, Switzerland) Nov 2020Calixarenes and related macrocycles have been shown to have antimicrobial effects since the 1950s. This review highlights the antimicrobial properties of almost 200... (Review)
Review
Calixarenes and related macrocycles have been shown to have antimicrobial effects since the 1950s. This review highlights the antimicrobial properties of almost 200 calixarenes, resorcinarenes, and pillararenes acting as prodrugs, drug delivery agents, and inhibitors of biofilm formation. A particularly important development in recent years has been the use of macrocycles with substituents terminating in sugars as biofilm inhibitors through their interactions with lectins. Although many examples exist where calixarenes encapsulate, or incorporate, antimicrobial drugs, one of the main factors to emerge is the ability of functionalized macrocycles to engage in multivalent interactions with proteins, and thus inhibit cellular aggregation.
Topics: Amino Acid Motifs; Animals; Anti-Infective Agents; Biofilms; Calixarenes; Drug Delivery Systems; Glycosylation; Humans; Lectins; Metals; Nanoparticles; Oxazoles; Phenylalanine; Prodrugs; Solubility; Sulfonamides; Thiadiazoles; Thiazoles; Vancomycin; Water
PubMed: 33167339
DOI: 10.3390/molecules25215145 -
ACS Chemical Neuroscience Oct 2018Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) are psychostimulants that have long been... (Review)
Review
Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) are psychostimulants that have long been listed in Schedules IV and I of the UN Convention on Psychotropic Substances of 1971. However, a range of psychoactive analogues exist that are not internationally controlled and therefore often classified as new psychoactive substances (NPS). Aminorex analogues encompass failed pharmaceuticals that reemerged as drugs of abuse, and newly synthesized substances that were solely designed for recreational use by clandestine chemists. NPS, sometimes also referred to as "designer drugs" in alignment with a phenomenon arising in the early 1980s, serve as alternatives to controlled drugs. Aminorex and its derivatives interact with monoaminergic neurotransmission by interfering with the function of monoamine transporters. Hence, these compounds share pharmacological and neurochemical similarities with amphetamines and cocaine. The consumption of aminorex, 4-methylaminorex and 4,4'-dimethylaminorex (4-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine) has been associated with adverse events including death, bestowing an inglorious fame on aminorex-derived drugs. In this Review, a historical background is presented, as well as an account of the pharmacodynamic and pharmacokinetic properties of aminorex and various analogues. Light is shed on their misuse as drug adulterants of well-established drugs on the market. This Review not only provides a detailed overview of an abused substance-class, but also emphasizes the darkest aspect of the NPS market, i.e., deleterious side effects that arise from the ingestion of certain NPS, as knowledge of the pharmacology, the potency, or the identity of the active ingredients remains obscure to NPS users.
Topics: Aminorex; Central Nervous System Stimulants; Designer Drugs; History, 20th Century; History, 21st Century; Humans
PubMed: 30269490
DOI: 10.1021/acschemneuro.8b00415 -
International Journal of Molecular... Aug 2022Leishmaniasis is a neglected tropical disease that kills more than 20,000 people each year. The chemotherapy available for the treatment of the disease is limited, and...
Leishmaniasis is a neglected tropical disease that kills more than 20,000 people each year. The chemotherapy available for the treatment of the disease is limited, and novel approaches to discover novel drugs are urgently needed. Herein, 2D- and 4D-quantitative structure-activity relationship (QSAR) models were developed for a series of oxazole and oxadiazole derivatives that are active against , the causative agent of visceral leishmaniasis. A clustering strategy based on structural similarity was applied with molecular fingerprints to divide the complete set of compounds into two groups. Hierarchical clustering was followed by the development of 2D- ( = 0.90, pred = 0.82) and 4D-QSAR models ( = 0.80, pred = 0.64), which showed improved statistical robustness and predictive ability.
Topics: Antiprotozoal Agents; Cluster Analysis; Humans; Leishmaniasis, Visceral; Oxadiazoles; Oxazoles; Quantitative Structure-Activity Relationship
PubMed: 36012163
DOI: 10.3390/ijms23168898