RAD001 – Everolimus by another name

 

The mTOR pathway

In clinical terms the mTOR protein was one of the most significant discovers in recent times. This protein similar in nature to the lipid kinases exhibits multi-domain serine/threonine kinase activity, by binding to a series of cellular and extracellular ligands functions of cellular growth and gene transcription are regulated. Ligands that can initiate mTOR activity include growth factors such as insulin and phorbol 12-myristate 13-acetate (PMA). Effects of activation can include the regulation of DNA repair, modification of cellular growth activities, regulation of its own activity and trigger cascades in the downstream pathways.

mTOR kinase inhibitors have been under development since the discovery of Rapamycin which demonstrated significant immunosuppression abilities. RAD001 was developed from derivatization of the side chains of rapamycin and has demonstrated significant biological activity in its own right. Used mostly in the clinical maintenance of transplant patients, these chemicals also demonstrated anti-tumor activity. Intense research has focused on their activity in mTOR inhibition in diseases of metabolic and proliferation functions. In terms of success RAD001 has been registered for two clinical conditions by the FDA and is under clinical trials in a wide range of diseases, mostly cancerous. The RAD001 mTOR inhibitor is a molecule which represents a move forward in terms of treatment of some of the most resistant and devastating conditions in the clinic today.

RAD001: Properties and Availability

With rapamycin as a template derivatives were screened for biological activity more specific and more effective than that being observed for Rapamycin. With adaptation of the side chain dimethoxycyclohexane side chain linked to the polyketide structure of the molecule the biological focus and activity can be adjusted. RAD001 is 1^st generation derivative of rapamycin that has been demonstrated to be an inhibitor of mTOR1 (FRAP1)[1] in addition to being a substrate for CYP3A4[2]. RAD001 is under the portfolio of Novartis’s pipeline drugs and it is marketed under several trade and research names (Everolimus, Afinitor, Zortress or Certican, OSI-RAD001 or SDZ-RAD). Activity of RAD001 is again mainly focused on its immunosuppression abilities but anti-tumor activities have been established. The RAD001 structure is complex and the synthesis route for production utilizes both multistage fermentation processes and chemical derivatization of the purified product (semisynthesis) [3]. Being soluble in both DMSO and alcohols (100mg/ml max) enables oral formulations to be marketed but RAD001 solubility in water or buffers is limited presenting problems in the research arena. Being determined to be a specific inhibitor of mTOR1 and demonstrating no activity towards mTOR 2 the RAD001 IC50 is in the range of 1-2 nM. When in solution RAD001 is considered slightly unstable and recommended to be stored at -20°C in daily use aliquots for a maximum of 3 months. The solid form of RAD001 is a lyophilized powder which can be kept stable for a minimum of 2 years at -20°C. Researchers can buy RAD001 in a range of package sizes under the name of Everolimus from most biochemical suppliers. RAD001 suppliers have a large range in quality (purity) and RAD001 cost that seem to be independent of each other. The RAD001 price of a 50 mg vial can range from $179 up to $800 but purity can range from 97 -99%.

RAD001: Clinical status

The level of research currently being under taken by scientist with RAD001 is vast. The potential of RAD001 to help in the treatment of a number of devastating diseases is significant and it is in RAD001 clinical trials as a single therapy and in combination with a wide variety of traditional treatments. For example in breast cancer it can be used in combination with Elrotinib, Paclitaxel, Docetaxel, Letrozole, Fulvestrant, Tratuzumab and Cisplatin [4]. Focuing on patients over expressing HER2 (which is quite significant in breast cancer) RAD001 has demonstrate some significant results.

References

 

    1.    Dumont FJ. Everolimus. Novartis. Curr Opin Investig Drugs 2001; 2(9):1220-1234.

    2.    Kuhn B, Jacobsen W et al. Metabolism of sirolimus and its derivative everolimus by cytochrome P450 3A4: insights from docking, molecular dynamics, and quantum chemical calculations. J Med Chem 2001; 44(12):2027-2034.

    3.    Kennedy J. Mutasynthesis, chemobiosynthesis, and back to semi-synthesis: combining synthetic chemistry and biosynthetic engineering for diversifying natural products. Nat Prod Rep 2008; 25(1):25-34.

    4.    Moulder S, Gladish G et al. A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer. Cancer 2011.