Everolimus

Chemical Identity

Property	Value
Chemical Formula	C53H83NO14
Molecular Weight	958.22 Da
CAS Number	159351-69-6
Peptide Class	Macrolide (mTOR Inhibitor)
Origin	Semi-synthetic (from sirolimus)

Structure

Everolimus is a derivative of sirolimus with a 2-hydroxyethyl ether substitution at position 40. This modification improves oral bioavailability and aqueous solubility while maintaining the mTOR-inhibitory pharmacophore. The molecule retains the pipecolic acid moiety and triene system of the parent compound.

Mechanism of Action

Like sirolimus, everolimus binds FKBP12 and inhibits mTORC1, blocking cell cycle progression from G1 to S phase. In oncology, mTOR inhibition reduces translation of proteins required for cell proliferation, angiogenesis (VEGF), and glucose metabolism. In transplantation, it suppresses T-cell and B-cell proliferation.

Clinical Applications

• Renal cell carcinoma: Second-line after VEGF-targeted therapy
• Neuroendocrine tumors: Pancreatic, GI, and lung NETs
• Tuberous sclerosis: SEGAs, renal angiomyolipomas, AML
• Breast cancer: HR+/HER2- advanced disease with exemestane
• Organ transplant: Kidney and liver rejection prevention

Pharmacokinetics

• Half-life: 30 hours
• Tmax: 1-2 hours
• Bioavailability: 16%
• Metabolism: CYP3A4 (primary)
• Protein binding: 74%
• Route: Oral (tablets, tablets for suspension)

Safety and Side Effects

Stomatitis (most common, 44%), rash, fatigue, diarrhea, pneumonitis (non-infectious), hyperglycemia, hyperlipidemia, and myelosuppression. Regular monitoring of blood glucose, lipids, and pulmonary function recommended.

References

• Motzer, R.J., et al. (2008). Everolimus for advanced renal cell carcinoma. New England Journal of Medicine, 359, 189-199.
• Yao, J.C., et al. (2011). Everolimus for advanced pancreatic NETs. New England Journal of Medicine, 364, 514-523.