Sirolimus

Sirolimus
Names
Trade namesRapamune
Other namesRapamycin
IUPAC name
  • (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,
    30S,32S,35R)-1,18-dihydroxy-12-{(2R)-1-[(1S,3R,
    4R)-4-hydroxy-3-methoxycyclohexyl]-2-propanyl}-
    19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-
    11,36-dioxa-4-azatricyclo[30.3.1.0~4,9~]hexatria
    conta-16,24,26,28-tetraene-2,3,10,14,20-pentone
Clinical data
Drug classmTOR inhibitor[1]
Main usesPrevent organ transplant rejection, treat lymphangioleiomyomatosis[1][2]
Side effectsInfection, fever, poor wound healing, diabetes, protein in the urine, rash, swelling[2]
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth
    External links
    US NLMSirolimus
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability14% (oral solution), lower with high-fat meals; 18% (tablet), higher with high-fat meals[3]
    Protein binding92%
    MetabolismHepatic
    Elimination half-life57–63 hours[4]
    ExcretionMostly faecal
    Chemical and physical data
    FormulaC51H79NO13
    Molar mass914.187 g·mol−1
    3D model (JSmol)
    Solubility in water0.0026 [5] mg/mL (20 °C)
    SMILES
    • O[C@@H]1CC[C@H](C[C@H]1OC)C[C@@H](C)[C@@H]4CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(/C)[C@@H](OC)C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N3CCCC[C@H]3C(=O)O4
    InChI
    • InChI=1S/C51H79NO13/c1-30-16-12-11-13-17-31(2)42(61-8)28-38-21-19-36(7)51(60,65-38)48(57)49(58)52-23-15-14-18-39(52)50(59)64-43(33(4)26-37-20-22-40(53)44(27-37)62-9)29-41(54)32(3)25-35(6)46(56)47(63-10)45(55)34(5)24-30/h11-13,16-17,25,30,32-34,36-40,42-44,46-47,53,56,60H,14-15,18-24,26-29H2,1-10H3/b13-11+,16-12+,31-17+,35-25+/t30-,32-,33-,34-,36-,37+,38+,39+,40-,42+,43+,44-,46-,47+,51-/m1/s1 checkY
    • Key:QFJCIRLUMZQUOT-HPLJOQBZSA-N checkY

    Sirolimus, also known as rapamycin, is a medication primarily used to prevent organ transplant rejection and treat lymphangioleiomyomatosis.[1][2] For kidney transplant it is a second line treatment.[6] It is taken by mouth.[1]

    Common side effects include infection, fever, poor wound healing, diabetes, protein in the urine, rash, and swelling.[2] Other side effects may include lymphoma, anaphylaxis, angioedema, kidney problems, and progressive multifocal leukoencephalopathy.[1] It is an mTOR inhibitor and works by decreasing the activation of T cells and B cells.[1]

    Sirolimus was isolated in 1972 and approved for medical use in the United States in 1999 and Europe in 2001.[1][7][2] It is available as a generic medication. A month of treatment in the United States at 2 mg per day costs about 225 USD as of 2021.[8] This amount in the United Kingdom costs the NHS £172.[6] It is sold under the brand name Rapamune.[1]

    Medical uses

    Sirolimus is indicated for the prevention of organ transplant rejection and for the treatment of lymphangioleiomyomatosis (LAM).[9]

    Prevention of transplant rejection

    See also: Organ rejection and Immunosuppression § Deliberately induced

    The chief advantage sirolimus has over calcineurin inhibitors is its low toxicity toward kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even kidney failure; this can be avoided by using sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome, as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used. However, on 7 October 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use.[10][11] In 2009, the FDA notified healthcare professionals that a clinical trial conducted by Wyeth showed an increased mortality in stable liver transplant patients after switching from a calcineurin inhibitor-based immunosuppressive regimen to sirolimus.[12]

    Sirolimus can also be used alone, or in conjunction with a calcineurin inhibitor (such as tacrolimus), and/or mycophenolate mofetil, to provide steroid-free immunosuppression regimens. Impaired wound healing and thrombocytopenia are possible side effects of sirolimus; therefore, some transplant centers prefer not to use it immediately after the transplant operation, but instead administer it only after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined, and it remains the subject of a number of ongoing clinical trials.[13]

    Lymphangioleiomyomatosis

    On 28 May 2015, the FDA approved sirolimus to treat lymphangioleiomyomatosis (LAM), a rare, progressive lung disease that primarily affects women of childbearing age. This made sirolimus the first drug approved to treat this disease.[14] LAM involves lung tissue infiltration with smooth muscle-like cells with mutations of the tuberous sclerosis complex gene (TSC2). Loss of TSC2 gene function activates the mTOR signaling pathway, resulting in the release of lymphangiogenic growth factors. Sirolimus blocks this pathway.[9]

    The safety and efficacy of sirolimus treatment of LAM were investigated in clinical trials that compared sirolimus treatment with a placebo group in 89 patients for 12 months. The patients were observed for 12 months after the treatment had ended. The most commonly reported side effects of sirolimus treatment of LAM were mouth and lip ulcers, diarrhea, abdominal pain, nausea, sore throat, acne, chest pain, leg swelling, upper respiratory tract infection, headache, dizziness, muscle pain and elevated cholesterol. Serious side effects including hypersensitivity and swelling (edema) have been observed in renal transplant patients.[14]

    While sirolimus was considered for treatment of LAM, it received orphan product designation status because LAM is a rare condition. Development for the product was partially supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.[14]

    The safety of LAM treatment by sirolimus in people younger than 18 years old has not been tested.[9]

    Vascular malformations

    Sirolimus is used to treat vascular malformations. Treatment with sirolimus can decrease pain and the fullness of vascular malformations, improve coagulation levels, and slow the growth of abnormal lymphatic vessels.[15] Sirolimus is a relatively new medical therapy for the treatment of vascular malformations,[16] in recent years, sirolimus has emerged as a new medical treatment option for both vascular tumors and vascular malformations, as a mammalian target of rapamycin (mTOR), capable of integrating signals from the PI3K/AKT pathway to coordinate proper cell growth and proliferation. Hence, sirolimus is ideal for “proliferative” vascular tumors through the control of tissue overgrowth disorders caused by inappropriate activation of the PI3K/AKT/mTOR pathway as an antiproliferative agent.[17]

    Sirolimus is used especially to treat lymphatic malformation.

    Coronary stents

    Further information: Drug-eluting stent

    A sirolimus-eluting coronary stent is marketed under the tradename Cypher.[18] However, this kind of stent may increase the risk of vascular thrombosis.[19]

    Dosage

    It is generally take at 2 mg per day; though the dose may be adjusted based on blood levels.[2]

    Contraindications

    Sirolimus is contraindicated in individuals with a known hypersensitivity to the drug.[9]

    Side effects

    The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in clinical studies of organ rejection prophylaxis in individuals with kidney transplants include: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, increased creatinine, fever, urinary tract infection, anemia, arthralgia, and thrombocytopenia.[9]

    The most common adverse reactions (≥20% occurrence, leading to an 11% treatment discontinuation rate) observed with sirolimus in clinical studies for the treatment of lymphangioleiomyomatosis are: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, chest pain, stomatitis, nasopharyngitis, acne, upper respiratory tract infection, dizziness, and myalgia.[9]

    • Folliculitis induced by sirolimus
    • Folliculitis induced by sirolimus
    • Folliculitis induced by sirolimus

    The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant:[9]

    System Adverse effects
    Body as a WholeSepsis, lymphocele, herpes zoster infection, herpes simplex infection
    CardiovascularVenous thromboembolism (pulmonary embolism and deep venous thrombosis), rapid heart rate
    DigestiveStomatitis
    Hematologic/LymphaticThrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia
    MetabolicAbnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes
    MusculoskeletalBone necrosis
    RespiratoryPneumonia, epistaxis
    SkinMelanoma, squamous cell carcinoma, basal cell carcinoma
    UrogenitalPyelonephritis, ovarian cysts, menstrual disorders (amenorrhea and menorrhagia)

    Diabetes

    While sirolimus inhibition of mTORC1 appears to mediate the drug's benefits, it also inhibits mTORC2, which results in diabetes-like symptoms.[20] This includes decreased glucose tolerance and insensitivity to insulin.[21] Sirolimus treatment may additionally increase the risk of type 2 diabetes.[22] In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or analogs such as everolimus or temsirolimus.[23]

    Lungs

    Lung toxicity is a serious complication associated with sirolimus therapy,[24][25][26][27][28][29][30] especially in the case of lung transplants.[31] The mechanism of the interstitial pneumonitis caused by sirolimus and other macrolide MTOR inhibitors is unclear, and may have nothing to do with the mTOR pathway.[32][33][34] The interstitial pneumonitis is not dose-dependent, but is more common in patients with underlying lung disease.[24][35]

    Infection

    There have been warnings about the use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections.[9][36]

    Cancer

    According to the FDA prescribing information, sirolimus may increase an individual's risk for contracting skin cancers from exposure to sunlight or UV radiation, and risk of developing lymphoma.[9] In studies, the skin cancer risk under sirolimus was lower than under other immunosuppressants such as azathioprine and calcineurin inhibitors, and lower than under placebo.[37][38]

    Wound healing

    Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have a body mass index in excess of 30 kg/m2 (classified as obese).[9]

    Interactions

    Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump; hence, inhibitors of either protein may increase sirolimus concentrations in blood plasma, whereas inducers of CYP3A4 and P-gp may decrease sirolimus concentrations in blood plasma.[9]

    Pharmacology

    Pharmacodynamics

    See also: mTOR inhibitors

    Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Sirolimus inhibits IL-2 and other cytokine receptor-dependent signal transduction mechanisms, via action on mTOR, and thereby blocks activation of T and B cells. Ciclosporin and tacrolimus inhibit the secretion of IL-2, by inhibiting calcineurin.[13]

    The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mTOR (mammalian Target Of Rapamycin, rapamycin being another name for sirolimus) pathway by directly binding to mTOR Complex 1 (mTORC1).[13]

    mTOR has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2.[39][13]

    Pharmacokinetics

    Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump.[9] It has an elimination half-life of 57–63 hours.[4]

    The absorption of sirolimus into the blood stream from the intestine varies widely between patients, with some patients having up to eight times more exposure than others for the same dose. Drug levels are, therefore, taken to make sure patients get the right dose for their condition.[13] This is determined by taking a blood sample before the next dose, which gives the trough level. However, good correlation is noted between trough concentration levels and drug exposure, known as area under the concentration-time curve, for both sirolimus (SRL) and tacrolimus (TAC) (SRL: r2 = 0.83; TAC: r2 = 0.82), so only one level need be taken to know its pharmacokinetic (PK) profile. PK profiles of SRL and of TAC are unaltered by simultaneous administration. Dose-corrected drug exposure of TAC correlates with SRL (r2 = 0.8), so patients have similar bioavailability of both.[40]

    Chemistry

    Sirolimus is a natural product and macrocyclic lactone.[4]

    Biosynthesis

    The biosynthesis of the rapamycin core is accomplished by a type I polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS). The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three multienzymes, RapA, RapB, and RapC, which contain a total of 14 modules (figure 1). The three multienzymes are organized such that the first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the biosynthesis of the linear polyketide are in RapC.[41] Then, the linear polyketide is modified by the NRPS, RapP, which attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, prerapamycin.[42]

    Figure 1: Domain organization of PKS of rapamycin and biosynthetic intermediates
    Figure 2: Prerapamycin, unbound product of PKS and NRPS
    Figure 3: Sequence of "tailoring" steps, which convert unbound prerapamycin into rapamycin
    Figure 4: Proposed mechanism of lysine cyclodeaminase conversion of L-lysine to L-pipecolic acid

    The core macrocycle, prerapamycin (figure 2), is then modified (figure 3) by an additional five enzymes, which lead to the final product, rapamycin. First, the core macrocycle is modified by RapI, SAM-dependent O-methyltransferase (MTase), which O-methylates at C39. Next, a carbonyl is installed at C9 by RapJ, a cytochrome P-450 monooxygenases (P-450). Then, RapM, another MTase, O-methylates at C16. Finally, RapN, another P-450, installs a hydroxyl at C27 immediately followed by O-methylation by Rap Q, a distinct MTase, at C27 to yield rapamycin.[43]

    The biosynthetic genes responsible for rapamycin synthesis have been identified. As expected, three extremely large open reading frames (ORF's) designated as rapA, rapB, and rapC encode for three extremely large and complex multienzymes, RapA, RapB, and RapC, respectively.[41] The gene rapL has been established to code for a NAD+-dependent lysine cycloamidase, which converts L-lysine to L-pipecolic acid (figure 4) for incorporation at the end of the polyketide.[44][45] The gene rapP, which is embedded between the PKS genes and translationally coupled to rapC, encodes for an additional enzyme, an NPRS responsible for incorporating L-pipecolic acid, chain termination and cyclization of prerapamycin. In addition, genes rapI, rapJ, rapM, rapN, rapO, and rapQ have been identified as coding for tailoring enzymes that modify the macrocyclic core to give rapamycin (figure 3). Finally, rapG and rapH have been identified to code for enzymes that have a positive regulatory role in the preparation of rapamycin through the control of rapamycin PKS gene expression.[46] Biosynthesis of this 31-membered macrocycle begins as the loading domain is primed with the starter unit, 4,5-dihydroxocyclohex-1-ene-carboxylic acid, which is derived from the shikimate pathway.[41] Note that the cyclohexane ring of the starting unit is reduced during the transfer to module 1. 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.

    History

    It is produced by the bacterium Streptomyces hygroscopicus and was isolated in 1972 by Surendra Nath Sehgal and colleagues from samples of Streptomyces hygroscopicus found on Easter Island.[7][47] The compound was originally named rapamycin after the native name of the island, Rapa Nui.[48] Sirolimus was initially developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit mTOR. It was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune by Pfizer (formerly by Wyeth).

    Research

    A plaque, written in Portuguese, commemorating the discovery of sirolimus on Easter Island, near Rano Kau

    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[49] or otherwise promote tumor regression in clinical trials.[50] Sirolimus seems to lower the cancer risk in some transplant patients.[51]

    Sirolimus was shown to inhibit the progression of dermal Kaposi's 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.[52]

    A combination therapy of doxorubicin and sirolimus has been shown to drive Akt-positive lymphomas into remission in mice. Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the cytotoxic effects of chemotherapy drugs, such as doxorubicin or cyclophosphamide. Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy. Bcl-2-positive lymphomas were completely resistant to the therapy; eIF4E-expressing lymphomas are not sensitive to sirolimus.[53][54][55][56]

    Tuberous sclerosis

    Sirolimus also shows promise in treating tuberous sclerosis complex (TSC), a congenital disorder that leaves sufferers prone to benign tumor growth in the brain, heart, kidneys, skin, and other organs. After several studies conclusively linked mTOR inhibitors to remission in TSC tumors, specifically subependymal giant-cell astrocytomas in children and angiomyolipomas in adults, many US doctors began prescribing sirolimus (Wyeth's Rapamune) and everolimus (Novartis's RAD001) to TSC patients off-label. Numerous clinical trials using both rapamycin analogs, involving both children and adults with TSC, are underway in the United States.[57]

    Most studies thus far have noted that tumors often regrew when treatment stopped.

    Facial angiofibromas occur in 80% of patients with TSC, and the condition is very disfiguring. A retrospective review of English-language medical publications reporting on topical sirolimus treatment of facial angiofibromas found sixteen separate studies with positive patient outcomes after using the drug. The reports involved a total of 84 patients, and improvement was observed in 94% of subjects, especially if treatment began during the early stages of the disease. Sirolimus treatment was applied in several different formulations (ointment, gel, solution, and cream), ranging from 0.003 to 1% concentrations. Reported adverse effects included one case of perioral dermatitis, one case of cephalea, and four cases of irritation.[58]

    Effects on longevity

    mTOR, specifically mTORC1, was first shown to be important in aging in 2003, in a study on worms; sirolimus was shown to inhibit and slow aging in worms, yeast, and flies, and then to improve the condition of mouse models of various diseases of aging.[59] Sirolimus was first shown to extend lifespan in wild-type mice in a study published by NIH investigators in 2009; the studies have been replicated in mice of many different genetic backgrounds.[59] A study published in 2020 found late-life rapamycin dosing schedules enhanced mouse lifespan in a sex-specific manner where limited rapamycin exposure enhanced male lifespan but not female, providing evidence for sex differences in rapamycin response.[60] The results are further supported by the finding that genetically modified mice with impaired mTORC1 signalling live longer.[59] The known adverse effects caused by sirolimus and marketed analogs at the doses used in transplant regimens, especially the increased risk of infection due to immunosuppression, as well as dose-dependent metabolic impairment, make it unlikely that chronic, long-term treatment with sirolimus could become a widely used anti-aging agent.[59]

    Rapamycin has complex effects on the immune system—while IL-12 goes up and IL-10 decreases, which suggests an immunostimulatory response, TNF and IL-6 are decreased, which suggests an immunosuppressive response. The duration of the inhibition and the exact extent to which mTORC1 and mTORC2 are inhibited play a role, but are not yet well understood.[61]

    SARS-CoV-2

    Rapamycin has been proposed as a treatment for severe acute respiratory syndrome coronavirus 2 insofar as its immunosuppressive effects could prevent or reduce the cytokine storm seen in very serious cases of COVID-19.[62] Moreover, inhibition of cell proliferation by rapamycin could reduce viral replication.[62]

    Atherosclerosis

    Rapamycin can accelerate degradation of oxidized LDL cholesterol in endothelial cells, thereby lowering the risk of atherosclerosis.[63] Oxidized LDL cholesterol is a major contributor to atherosclerosis.[64]

    Lupus

    As of 2016 studies in cells, animals, and humans have suggested that mTOR activation as process underlying systemic lupus erythematosus and that inhibiting mTOR with rapamycin may be a disease-modifying treatment.[65] As of 2016 rapamycin had been tested in small clinical trials in people with lupus.[65]

    Lymphatic malformation

    Lymphatic malformation is either a superficial, deep or mixed growth of lymphatic vessels. Treatment is limited to removal or destruction, however, the rate of recurrence is high. García M et al.[66] made a topical formulation of rapamycin, and conducted a small case series, involving 11 patients with superficial lymphatic malformations. The clinical appearance improved in all 11, and symptoms improved in 9 of the 11. The average follow-up time was 16.1 months, indicating that topical rapamycin, ranging from .4-1.0% is promising for management of superficial lymphatic malformations.

    Graft-versus-host disease

    Due to its immunosuppressant activity, Rapamycin has been assessed as prophylaxis or treatment agent of Graft-versus-host disease (GVHD), a complication of hematopoietic stem cell transplantation. While contrasted results were obtained in clinical trials,[67] pre-clinical studies have shown that Rapamycin can mitigate GVHD by increasing the proliferation of regulatory T cells, inhibiting cytotoxic T cells and lowering the differentiation of effector T cells.[68][69]

    Biology research

    Rapamycin is used in biology research as an agent for chemically induced dimerization.[70] In this application, rapamycin is added to cells expressing two fusion constructs, one of which contains the rapamycin-binding FRB domain from mTOR and the other of which contains an FKBP domain. Each fusion protein also contains additional domains that are brought into proximity when rapamycin induces binding of FRB and FKBP. In this way, rapamycin can be used to control and study protein localization and interactions.

    References

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    3. ↑ Buck ML (2006). "Immunosuppression With Sirolimus After Solid Organ Transplantation in Children". Pediatric Pharmacotherapy. 12 (2). Archived from the original on 18 April 2020. Retrieved 11 June 2021.
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    11. ↑ Koprowski G (7 February 2012). Nanotechnology in Medicine: Emerging Applications. Momentum Press. ISBN 978-1-60650-250-1. Archived from the original on 30 September 2020. Retrieved 11 June 2021.
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    20. ↑ Lamming, Dudley W.; Ye, Lan; Katajisto, Pekka; Goncalves, Marcus D.; Saitoh, Maki; Stevens, Deanna M.; Davis, James G.; Salmon, Adam B.; Richardson, Arlan (30 March 2012). "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity". Science. 335 (6076): 1638–1643. Bibcode:2012Sci...335.1638L. doi:10.1126/science.1215135. ISSN 1095-9203. PMC 3324089. PMID 22461615.
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