Everolimus, as a mTOR inhibitor

by Selleckchem | Sep 26 2012

EVEROLIMUS
Everolimus, also known as RAD001 or SDZ RAD, is a orally active rapamycin analog with potent immunosuppressive activity. Similar with rapamycin, Everolimus is also identified as a potent inhibitor against mammalian target of rapamycin (mTOR). The preclinical trials in vitro and in vivo indicate that Everolimus as an immunosuppressant efficiently inhibits antigen-driven proliferation of human T-cell clones and prevents graft rejection in rat models of allotransplantation. [1] In addition, Everolimus as an mTOR inhibitor also shows potential anti-tumor activity for treatment of multiple cancers.

ACTION MECHANISM OF EVEROLIMUS

As is known, mTOR inhibitor Rapamycin binds to an intracellular protein called FK506-binding protein 12 (FKBP12), and the protein–drug complex further produces inhibitory effect on the kinase activity of mTOR. [2] In order to improve the pharmaceutical properties of Rapamycin including effects or safety, multiple derivatives of rapamycin have been synthesized and evaluated and thus Temsirolimus as well as Everolimus such are discovered and developed. [3] Similar with Rapamycin, Everolimus binds to FKBP12, forming a complex that inhibits mTOR kinase activity, and reduces the activity of the downstream effectors S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP)[2]. Subsequently, Everolimus produces the inhibitory effects on tumor cell proliferation and angiogenesis. Of which, the latter is mediated by inhibiting hypoxia-inducible factor 1-alpha (HIF1alpha) expression.[4]

CLINICAL TRIALS
Currently, Everolimus has been evaluated as an immunosuppressant or an anti-cancer agent in phase I and II clinical trials, and shows effective therapy results. According to the known study, Everolimus has been involved in the clinical trials of Organ Transplant - Rejection Prophylaxis. It is reported that Phase 4 clinical study of Everolimus on renal function in heart transplant recipients with established chronic Renal failure (COREV) has been active, and study of Everolimus on therapy of cytomegalovirus disease in renal transplant patients (Certi-CMV) is currently recruiting participants for Phase 2 clinical study. Besides, Everolimus is approved for therapy of various cancers, including advanced kidney cancer, progressive or metastatic pancreatic neuroendocrine tumors and breast cancer in post-menopausal women with advanced hormone-receptor positive, HER2-negative type cancer. At present, Phase III trials of Everolimus are under way in gastric cancer, hepatocellular carcinoma and lymphoma.
In addition, combination study of Everolimus and other drugs is in process, such as Everolimus in combination with Docetaxel and Cisplatin in patients with local-regional advanced head and neck cancer, Everolimus in combination with BEZ235 in patients with advanced solid tumors, Panobinostat in combination with Everolimus in patients with relapsed and refractory lymphoma, and so on. We will continue to follow up on the new clinical studies about Everolimus and the related combination therapy.

REFERENCES
[1]. Schuler W, et al. SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation. 1997, 64(1), 36-42.
[2]. Faivre S, et al. Current development of mTOR inhibitors as anticancer agents. Nature Rev. Drug Discov. 2006, 5, 671–688.
[3]. Rini B, et al. Temsirolimus. Nature Rev. Drug Discov. 2007, 6, 599–600.
[4]. Lane HA, et al. mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin. Cancer Res. 2009,15, 1612–1622.

Cat.No.	Product Name	Information
S1120	Everolimus	Everolimus is an mTOR inhibitor of FKBP12 with IC50 of 1.6-2.4 nM in a cell-free assay. Everolimus induces cell apoptosis and autophagy and inhibits tumor cells proliferation.
S1049	Y-27632 2HCl	Y-27632 2HCl is a selective ROCK1 and ROCK2 inhibitor with a K_i of 140 nM and 300nM in a cell-free assay, exhibits >200-fold selectivity over other kinases, including PKC, cAMP-dependent protein kinase, MLCK and PAK.
S1044	Temsirolimus	Temsirolimus is a specific mTOR inhibitor with IC50 of 1.76 μM in a cell-free assay. Temsirolimus induces autophagy and apoptosis.
S1148	Docetaxel	Docetaxel, an analog of paclitaxel, is an inhibitor of depolymerisation of microtubules by binding to stabilized microtubules.
S1166	Cisplatin	Cisplatin is an inorganic platinum complex, which is able to inhibit DNA synthesis by conforming DNA adducts in tumor cells. Cisplatin activates ferroptosis and induces autophagy.Solutions are unstable and should be fresh-prepared.DMSO is not recommended to dissolve platinum-based drugs, which can easily lead to drug inactivation.
S1099	SKLB4771 (FLT3-IN-1)	SKLB4771 is a potent and selective inhibitor of human receptor-type tyrosine-protein kinase FLT3 with IC50 of 10 nM.
S1033	Nilotinib	Nilotinib is a selective Bcr-Abl inhibitor with IC50 less than 30 nM in Murine myeloid progenitor cells. Nilotinib induces autophagy through AMPK activition.