RAPAMYCIN

Introduction: The mTOR pathway

Rapamycin is a molecule which was discovered as a byproduct of bacterial action in a soil sample from Easter Island. During extract screening it was observed that this molecule specifically targeted a previously unknown protein [1;2]. This protein was purified and characterized in an intensive series of research programs. The name given to this protein was the acronym mTOR (meaning “mammalian Target for Rapamycin”). The importance of this molecule was slowly uncovered as it demonstrated significant regulatory abilities in gene transcription and cellular growth processes. The unusual aspect of this protein was its structural resemblance to the lipid kinases but its multi faceted functions similar to the serine/threonine kinases [3]. Multiple domains were identified which responded to ligands directly from the extracellular systemic circulation and from indirect triggers from other pathways. Triggers initiated by Rapamycin mTOR inhibitor lead to adaptation of other mechanisms [4], building of scaffolds for DNA repair, actin organization [5], initiation of the start codon (AUG) in gene transcription [6] and to regulate its own activity [7;8].

Rapamycin: Properties and Availability

Rapamycin. Originally it was developed as a fungicide but other properties were discovered in relation to clinical activity which outweighed its fungicide effects. Rapamycin was determined to be a potent immunosuppressant and it is used extensively in suppresses transplant rejection. Rapamycin synthesis is an example of the industrial adaptation of biosysnthesis techniques and is a multistage fermentation process [9-12]. Rapamycin is being developed now by Pfizer but originally was introduced by Wyeth-Ayerst, it is marketed under the trade names of Rapamune and Sirolimus. The Rapamycin structure is based on a methoxy substituted cyclic diene trione and the Rapamycin molecular weight is 914.2. Soluble in DMSO and ethanol to a saturation of 50mg/ml Rapamycin solubility in water or buffered solutions is limited. The Rapamycin IC50 for purified mTOR is in the 1 -2 nM range but specific mTOR1 or mTOR2 IC50’s are not listed. Rapamycin is supplied as a lyophilized powder which can be stored at -20°C with an expiration date of 2 years. Rapamycin stability when in solution is unstable, it is recommended that all solutions be kept at -20°C for a maximum of 3 months with minimal thawing. Researchers can buy Rapamycin through a number of Rapamycin suppliers with the Rapamycin cost of a 50 mg vial ranging from $53 up to $1649 for the sterilized product. The range of the Rapamycin price is extreme and researchers should be aware of the fact.

Rapamycin: Clinical status and investigational progress

The range and breath of the effects determined for this molecule is vast, which is to be expected considering its role in the cellular pathways. Its highest volume use is as an immunosuppresser after transplant surgery where it is highly effective in preventing organ rejection [13-15], it was FDA approved in the maintenance therapy after kidney transplants, but is under investigation for a range of transplant activities. More recently it was realized that mTOR is a functional part of many of the pathways being investigated in terms of tumor development. Rapamycin was tested preclinically and found to posses potent anti tumor activity. Subsequently Rapamycin cancer analogues have been derivatized into analogues several of which have been FDA approved for the treatment of various solid tumor types, for example Everolimus. Rapamycin clinical trials have been initiated in lymphoma, glioblastoma, NSCLC, renal carcinoma, advanced solid tumors, diabetes (focusing on Macular disorders), metastatic cancer and osteosarcoma [16-23]. A topical Rapamycin form has even been used for a variety of facial and skin disorders [24-29]. Under the trade name Sirolimus, it has been approved for use as an immunosuppresser in the form of an oral solution showing clear clinical benefits.

References

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