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Phosphoinositide-dependent kinase-1 as an antifungal drug target

磷酸肌醇依赖性激酶 1 作为抗真菌药物靶点

基本信息

批准号：
8458933
负责人：
Damian J Krysan
金额：
$ 36.31万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8458933
关键词：
Anabolism Animal Model Anti-Infective Agents Antibiotics Antifungal Agents Antifungal Therapy Bacterial Infections Biology Candida Candida albicans Cell Wall Cells Chemicals Clinical Clinical Trials Communicable Diseases Cryptococcus neoformans Development Drug Industry Drug Targeting Goals HIV Human Human Activities Human Identifications Immune Immunity In Vitro Isatin Lead Mammalian Cell Mediating Meningitis Minimum Inhibitory Concentration measurement Molecular Morbidity - disease rate Mycoses Normal Cell Orthologous Gene Outcome Pathogenesis Patients Pharmaceutical Preparations Pharmacology Phosphotransferases Physiological Property Protein Kinase Protein Kinase Inhibitors Pyrazoles Research Resistance Resources Sepsis Signal Pathway Signal Transduction Structure Testing Therapeutic Toxic effect Work Yeasts base celecoxib design drug candidate drug discovery fungus high throughput screening human disease in vitro activity in vivo inhibitor/antagonist interest mortality novel phosphoinositide-dependent kinase 1 protein kinase inhibitor scaffold small molecule

项目摘要

PROJECT SUMMARY Invasive fungal infections are an important cause of morbidity and mortality for people with compromised immunity. Unfortunately, the mortality associated with invasive fungal infections remains unacceptably high. One of the contributing factors to this poor outcome is the fact that there are relatively few therapeutic options for the treatment of invasive fungal infections, particularly when compared to the number of antibiotics available for the treatment of bacterial infections. To identify new antifungal drug candidates, we have initiated a high throughput screening and chemical biology-based project to identify molecules that interfere with fungal cell wall biosynthesis. Application of this strategy has rapidly led to the identification of human phosphoinositide dependent kinase-1 (PDK1) inhibitors as highly active antifungal molecules in vitro. PDK1 inhibitors have been extensively developed as targeted anticancer molecules because of their low toxicity toward normal cells and, encouragingly, three of the PDK1 inhibitors identified in our preliminary work (UCN- 01, sunitinib and OSU-03012) have been, or are being, evaluated in human clinical trials. In order to develop the promising potential of PDK1/Pkh inhibitors as antifungal drugs, we will: characterize the molecular basis for the activity of mammalian PDK1 inhibitors toward fungal PDK1 orthologs (Aim 1); optimize the antifungal activity of two lead scaffolds (pyrazole and oxyindole/istatin) by structure-activity analysis (Aim 2); and determine the in vitro and in vivo efficacy of the novel PDK1 inhibitors in animal models (Aim 3). This focused research plan is designed to systematically evaluate the antifungal activity of human PDK1 inhibitor scaffolds and will hopefully lead to first-in-class antifungal molecules for additional development.

项目总结