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Journal ArticleDOI

Rapamycin (ay-22, 989), a new antifungal antibiotic i. taxonomy of the producing streptomycete and isolation of the active principle

01 Oct 1975-The Journal of Antibiotics (JAPAN ANTIBIOTICS RESEARCH ASSOCIATION)-Vol. 28, Iss: 10, pp 721-726
TL;DR: From its characteristic ultraviolet absorption spectrum rapamycin can be classified as a triene and its activity is compared with that of amphotericin B, candicidin and nystatin.
Abstract: A streptomycete was isolated from an Easter Island soil sample and found to inhibit Candida albicans, Microsporum gypseum and Trichophyton granulosum. The antibiotic-producing microorganism was characterized and identified as Streptomyces hygroscopicus. The antifungal principle was extracted with organic solvent from the mycelium, isolated in crystalline form and named rapamycin. Rapamycin is mainly active against Candida albicans; minimum inhibitory concentration against ten strains ranged from 0.02 to 0.2 mug/ml. Its apparent activity against Microsporum gypseum and Trichophyton granulosum is lower because of its instability in culture media on prolonged incubation required by these fungi. No activity was observed against gram-positive and gram-negative bacteria. Acute toxicity in mice is low.
Citations
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09 Mar 2017-Cell
TL;DR: Recent advances in understanding of mTOR function, regulation, and importance in mammalian physiology are reviewed and how the mTOR signaling network contributes to human disease is highlighted.

4,719 citations

Journal ArticleDOI
TL;DR: The potential of and challenges for the development of therapeutic agents that target this pathway in cancer are discussed and the potential and challenges in understanding of the PI3K pathway are highlighted.
Abstract: The phosphoinositide 3-kinase (PI3K) pathway is a key signal transduction system that links oncogenes and multiple receptor classes to many essential cellular functions, and is perhaps the most commonly activated signalling pathway in human cancer. This pathway therefore presents both an opportunity and a challenge for cancer therapy. Even as inhibitors that target PI3K isoforms and other major nodes in the pathway, including AKT and mammalian target of rapamycin (mTOR), reach clinical trials, major issues remain. Here, we highlight recent progress that has been made in our understanding of the PI3K pathway and discuss the potential of and challenges for the development of therapeutic agents that target this pathway in cancer.

2,315 citations

Journal ArticleDOI
TL;DR: It is postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.
Abstract: Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches — with 28 and 17 of these drugs coming from the two approaches, respectively — in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.

1,552 citations

Journal ArticleDOI
TL;DR: Recent work identifying two structurally and functionally distinct mTOR-containing multiprotein complexes and TSC1/2, rheb, and AMPK as upstream regulators of mTOR is beginning to reveal how mTOR can sense diverse signals and produce a myriad of responses.

1,543 citations

References
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Journal Article
TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.

289,852 citations

Journal ArticleDOI
TL;DR: The methods used by collaborators in the ISP for emendation of descriptions of type and neotype strains of the genus Streptomyces (Actinomycetales) are presented.
Abstract: The methods used by collaborators in the International Streptomyces Project (ISP) for emendation of descriptions of type and neotype strains of the genus Streptomyces (Actinomycetales) are presented.

5,184 citations

Journal ArticleDOI
TL;DR: Serum specimens are tested directly rather than diluting them to a narrow range of antibiotic concentrations, possible because of a procedure for calculations that recognizes the curvilinear relationship between zone sizes and antibiotic concentrations.
Abstract: Large glass plates are used for this modified agar-well diffusion assay method, allowing up to 81 replications on a single plate With a specially designed agar punch, it is possible to prepare the small agar wells very quickly The saving in serum resulting from fewer replications of standards with the large plates, and the small volume of the agar wells, makes it economically feasible to use pooled human serum for the standard antibiotic solutions Methods are described for preparing the standard solutions, and for providing controls for the deterioration of standards and unknowns Procedures for preparing and maintaining the commonly used assay organisms are presented Serum specimens are tested directly rather than diluting them to a narrow range of antibiotic concentrations This is possible because of a procedure for calculations that recognizes the curvilinear relationship between zone sizes and antibiotic concentrations Adaptation of this method to a number of the commonly used antibiotics is described With this method, it has been possible to test large numbers of clinical specimens in a minimal time, and with accuracy consistently better than 10% Images

997 citations