Everolimus

Everolimus

Systematic (IUPAC) name
dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
Clinical data
Licence data	US FDA:link
Pregnancy cat.	D(US)
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Half-life	~30 hours[1]
Identifiers
CAS number	159351-69-6 Y
ATC code	L01XE10 L04AA18
PubChem	CID 6442177
DrugBank	DB01590
ChemSpider	21106307 Y
UNII	9HW64Q8G6G Y
KEGG	D02714 Y
ChEMBL	CHEMBL1201755 N
Synonyms	42-O-(2-hydroxyethyl)rapamycin
Chemical data
Formula	C53H83NO14
Mol. mass	958.224 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19-38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35(4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6)48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43-46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/b13-11+,16-12+,33-17+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1 Y Key:HKVAMNSJSFKALM-GKUWKFKPSA-N Y
N(what is this?)  (verify)

Everolimus (RAD-001) is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor.

It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.

It is marketed by Novartis under the tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine, and Afinitor in oncology.

Approvals and indications

Everolimus is approved for various conditions:

• Advanced kidney cancer (approved in March 2009)^[2]
• Prevention of organ rejection after renal transplant(April 2010)^[3]
• Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients who are not suitable for surgical intervention (October 2010)^[4]
• Progressive or metastatic pancreatic neuroendocrine tumors not surgically removable (May 2011)^[5]

Clinical trials

As of October 2010^[update], Phase III trials are under way in breast cancer, gastric cancer, hepatocellular carcinoma and lymphoma.^[6]

Interim phase III trial results in 2011 show that adding Afinitor (everolimus) to exemestane therapy against advanced breast cancer can significantly improve progression-free survival compared with exemestane therapy alone.^[7]

Mechanism

In a similar fashion to other mTOR inhibitors its effect is solely on the mTORC1 protein and not on the mTORC2 protein. This can lead to a hyper-activation of the kinase AKT via inhibition on the mTORC1 negative feedback loop while not inhibiting the mTORC2 positive feedback to AKT. This AKT elevation can lead to longer survival in some cell types.

Role in heart transplantation

Everolimus may have a role in heart transplantation as it has been shown to reduce chronic allograft vasculopathy in such transplants. It also may have a similar role to sirolimus in kidney and other transplants.^[8]

Because hypercholesterolemia and hypertriglyceridemia have been reported, monitoring of blood lipid level is recommended.

Use in vascular stents

Everolimus is used in drug-eluting coronary stents as an immunosuppressant to prevent restenosis. Abbott Vascular produces an everolimus-eluting stent called the Xience V. It utilizes the Multi-Link Vision cobalt chromium stent platform and Novartis' everolimus. The product is also currently an investigational device in the United States and Japan. It is also available under a private-label version called the PROMUS Everolimus-Eluting Coronary Stent System and it is currently available in most major European and Asia-Pacific markets.

References

1. ^ R.N Formica Jra, K.M Lorberb, A.L Friedmanb, M.J Biaa, F Lakkisa, J.D Smitha, M.I Lorber (March 2004). "The evolving experience using everolimus in clinical transplantation". Elsevier 36 (2): S495–S499. http://www.transplantation-proceedings.org/article/S0041-1345(04)00016-8/abstract. 
2. ^ "Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib" (Press release). Novartis. 2009-03-30. http://www.novartis.com/newsroom/media-releases/en/2009/1301801.shtml. Retrieved April 6, 2009. 
3. ^ "Novartis receives US FDA approval for Zortress (everolimus) to prevent organ rejection in adult kidney transplant recipients" (Press release). Novartis. 2010-04-22. http://www.novartis.com/newsroom/media-releases/en/2010/1406625.shtml. Retrieved April 26, 2010. 
4. ^ "Novartis’ Afinitor Cleared by FDA for Treating SEGA Tumors in Tuberous Sclerosis". 1 Nov 2010. http://www.genengnews.com/gen-news-highlights/novartis-afinitor-cleared-by-fda-for-treating-sega-tumors-in-tuberous-sclerosis/81244159/. 
5. ^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm
6. ^ http://www.genengnews.com/gen-news-highlights/novartis-afinitor-cleared-by-fda-for-treating-sega-tumors-in-tuberous-sclerosis/81244159/
7. ^ "Positive Trial Data Leads Novartis to Plan Breast Cancer Filing for Afinitor by Year End". 2011. http://www.genengnews.com/gen-news-highlights/positive-trial-data-leads-novartis-to-plan-breast-cancer-filing-for-afinitor-by-year-end/81245384/. 
8. ^ Eisen HJ, Tuzcu EM, Dorent R, et al. (August 2003). "Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients". N. Engl. J. Med. 349 (9): 847–58. doi:10.1056/NEJMoa022171. PMID 12944570. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12944570&promo=ONFLNS19. 

• Sedrani R, Cottens S, Kallen J, Schuler W (August 1998). "Chemical modification of rapamycin: the discovery of SDZ RAD". Transplant. Proc. 30 (5): 2192–4. doi:10.1016/S0041-1345(98)00587-9. PMID 9723437. http://linkinghub.elsevier.com/retrieve/pii/S0041-1345(98)00587-9.