ABSTRACT
Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest. Azo-PROTACs are light-controlled small-molecule tools for protein knockdown in cells. The light-induced configuration change can switch the active state to induce protein degradation activity, which can be reversely controlled by light exposure in intact cells. We compared the protein degradation abilities of Azo-PROTACs with different configurations and linker lengths. Using the stable form with the best degradation ability against the BCR-ABL fusion and ABL proteins in myelogenous leukemia K562 cells, we showed that Azo-PROTAC combines the potent protein knockdown and facile cell uptake properties of the small-molecule PROTAC with a reversible photoswitchability, offering a promising chemical knockdown strategy based on the light-induced reversible on/off properties.
Subject(s)
Azo Compounds/pharmacology , Dasatinib/analogs & derivatives , Dasatinib/pharmacology , Lenalidomide/analogs & derivatives , Lenalidomide/pharmacology , Adaptor Proteins, Signal Transducing/metabolism , Azo Compounds/chemical synthesis , Azo Compounds/radiation effects , Cell Line, Tumor , Dasatinib/radiation effects , Fusion Proteins, bcr-abl/metabolism , Humans , Lenalidomide/radiation effects , Ligands , Proteolysis/drug effects , Stereoisomerism , Ubiquitin-Protein Ligases , Ubiquitination/drug effects , Ultraviolet RaysABSTRACT
Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
Subject(s)
Antineoplastic Agents/pharmacology , Cytochrome P-450 Enzyme Inhibitors/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Pyridines/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/chemistry , Cytochrome P-450 Enzyme System/metabolism , Dose-Response Relationship, Drug , HCT116 Cells , HSP90 Heat-Shock Proteins/metabolism , Humans , Male , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
In recent years, wildlife conservation has attracted great public attention. However, substantial distinctions can be found in the prevailing concepts of wildlife conservation, particularly with the recent notion that emphasizes animal rights. Wildlife welfare and wildlife rights are not synonymous, with welfare more compatible with the reasonable and legal utilization of wildlife. The key to scientific wildlife conservation is the appropriate awareness and appreciation of the relationship between wildlife conservation and utilization and the theoretical basis of holism. Nevertheless, rational biases regarding the public's understanding of wildlife conservation and the spread of information via social media still exist. As such, expansion of the concept of scientific wildlife conservation requires the application of several measures. Wildlife conservation researchers should be regarded as the most important disseminators of scientifically-based information, with education in schools and universities of growing importance. Furthermore, the media should shoulder the social responsibility for the accurate dissemination of conservation information.
Subject(s)
Conservation of Natural Resources/methods , Information Dissemination/methods , Science , Animals , Biological Evolution , Education , HumansABSTRACT
Heat shock protein 90 (Hsp90) as a molecular target for oncology therapeutics has attracted much attention in the last decade. The Hsp90 multichaperone complex has important roles in the growth and/or survival of cancer cells. Cdc37, as a cochaperone, associates kinase clients to Hsp90 and promotes the development of malignant tumors. Disrupting the Hsp90-Cdc37 interaction provides an alternative strategy to inhibit the function of Hsp90 for cancer therapy. Celastrol, as a natural product, can disrupt the Hsp90-Cdc37 interaction and induce degradation of kinase clients. The study conducted here attempted to elucidate the structure-activity relationship of celastrol derivatives as Hsp90-Cdc37 disruptors and to improve the druglike properties. 23 celastrol derivatives were designed, synthesized, and the biological activities and physicochemical properties were determined. The derivative CEL20 showed improved Hsp90-Cdc37 disruption activity, anti-proliferative activities as well as druglike properties. Additionally, CEL20 induced clients degradation, cell cycle arrest and apoptosis in Panc-1 cells. This study can provide reference for the discovery of novel Hsp90-Cdc37 disruptors.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Chaperonins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Triterpenes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Cycle Proteins/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chaperonins/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HSP90 Heat-Shock Proteins/chemistry , Humans , Models, Molecular , Molecular Structure , Pentacyclic Triterpenes , Structure-Activity Relationship , Triterpenes/chemical synthesis , Triterpenes/chemistryABSTRACT
BACKGROUND: Neisseria meningitidis serogroup C has emerged as a cause of epidemic disease in Hefei. The establishment of serogroup C as the predominant cause of endemic disease has not been described. METHODS: We conducted national laboratory-based surveillance for invasive meningococcal disease during 2000-2010. Isolates were characterized by pulsed-field gel electrophoresis and multilocus sequence typing. RESULTS: A total of 845 cases of invasive meningococcal disease were reported. The incidence increased from 1.25 cases per 100,000 population in 2000 to 3.14 cases per 100,000 in 2003 (p < 0.001), and peaked at 8.43 cases per 100,000 in 2005. The increase was mainly the result of an increase in the incidence of serogroup C disease. Serogroup C disease increased from 2/23 (9%) meningococcal cases and 0.11 cases per 100,000 in 2000 to 33/58 (57%) cases and 1.76 cases per 100,000 in 2003 (p < 0.01). Patients infected with serogroup C had serious complications more frequently than those infected with other serogroups. Specifically, 161/493 (32.7%) cases infected with serogroup C had at least one complication. The case-fatality rate of serogroup C meningitis was 11.4%, significantly higher than for serogroup A meningitis (5.3%, p = 0.021). Among patients with meningococcal disease, factors associated with death in univariate analysis were age of 15-24 years, infection with serogroup C, and meningococcemia. CONCLUSIONS: The incidence of meningococcal disease has substantially increased and serogroup C has become endemic in Hefei. The serogroup C strain has caused more severe disease than the previously predominant serogroup A strain.
