The starting unit is then modified by a series of Claisen condensations with malonyl or methylmalonyl substrates, which are attached to an acyl carrier protein (ACP) and extend the polyketide by two carbons each. After each successive condensation, the growing polyketide is further modified according to enzymatic domains that are present to reduce and dehydrate it, thereby introducing the diversity of functionalities observed in rapamycin (figure 1). Once the linear polyketide is complete, L-pipecolic acid, which is synthesized by a lysine cycloamidase from an L-lysine, is added to the terminal end of the polyketide by an NRPS. Then, the NSPS cyclizes the polyketide, giving prerapamycin, the first enzyme-free product. The macrocyclic core is then customized by a series of post-PKS enzymes through methylations by MTases and oxidations by P-450s to yield rapamycin. Research
Cancer
The antiproliferative effects of sirolimus may have a role in treating cancer. When dosed appropriately, sirolimus can enhance the immune response to tumor targeting or otherwise promote tumor regression in clinical trials. Sirolimus seems to lower the cancer risk in some transplant patients.Sirolimus was shown to inhibit the progression of dermal Kaposis sarcoma in patients with renal transplants. Other mTOR inhibitors, such as temsirolimus (CCI-779) or everolimus (RAD001), are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma. However, these drugs have a higher rate of fatal adverse events in cancer patients than control drugs.A combination therapy of doxorubicin and sirolimus has been shown to drive Akt-positive lymphomas into remission in mice.
"Efficacy and safety of sirolimus in the treatment of vascular anomalies: A systematic review". Journal of Vascular Surgery. 71 (1): 318–327. doi:10.1016/j.jvs.2019.06.217. PMID 31676179. S2CID 207831199. Geeurickx M, Labarque V (September 2021). "A narrative review of the role of sirolimus in the treatment of congenital vascular malformations". Journal of Vascular Surgery. Venous and Lymphatic Disorders. 9 (5): 1321–1333. doi:10.1016/j.jvsv.2021.03.001. PMID 33737259. External links

"Sirolimus". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02494570 for "A Phase 2 Study of ABI-009 in Patients With Advanced Malignant PEComa (AMPECT)" at ClinicalTrials.gov