rapalogs

Rapalogs are macrolide compounds that are structural analogs of rapamycin (sirolimus). They inhibit the mechanistic target of rapamycin (mTOR), a central regulator of cell growth and metabolism. Rapalogs form a complex with FKBP12, which then inhibits mTOR complex 1 (mTORC1).

The main rapalogs are sirolimus, everolimus, temsirolimus, and ridaforolimus. They are used for immunosuppression in organ transplantation, especially kidney transplants. In cancer therapy, temsirolimus is approved for advanced renal cell carcinoma; everolimus is approved for advanced RCC, pancreatic neuroendocrine tumors, and tuberous sclerosis complex–related tumors such as subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma. Ridaforolimus has been studied in sarcoma and other solid tumors but does not have broad approval.

Mechanistically, mTORC1 inhibition reduces signaling through S6K1 and 4E-BP1, leading to decreased protein synthesis and cell proliferation. Rapalogs can also influence tumor angiogenesis and autophagy. Sensitivity to mTOR inhibition often relates to tumor genetics, including loss of TSC1/2 or PTEN. Prolonged exposure may affect mTORC2 in some contexts, contributing to metabolic effects.

Adverse effects are common and include mucositis, edema, hyperlipidemia, hyperglycemia, cytopenias, infections, wound-healing impairment, and interstitial pneumonitis. Drug interactions with CYP3A4 inhibitors or inducers can markedly alter drug levels, requiring monitoring of drug exposure and organ function. Use in pregnancy is generally avoided. Rapalogs are not universally effective across cancers, and resistance can develop.