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Revision as of 16:39, 12 October 2016

Sirolimus
Clinical data
Trade namesRapamune
Other namesRapamycin
License data
Pregnancy
category
  • AU: C
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability14% (oral solution), lower with high-fat meals; 18% (tablet), higher with high-fat meals[2]
Protein binding92%
MetabolismHepatic
Elimination half-life57–63 hours[3]
ExcretionMostly faecal
Identifiers
  • (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,
    26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,
    27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-
    [(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-
    1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-
    hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-
    oxaazacyclohentriacontine-1,5,11,28,29
    (4H,6H,31H)-pentone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.107.147 Edit this at Wikidata
Chemical and physical data
FormulaC51H79NO13
Molar mass914.172 g/mol g·mol−1
3D model (JSmol)
Solubility in water0.0026 [4] mg/mL (20 °C)
  • 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=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
  (verify)

Sirolimus (INN/USAN), also known as rapamycin, is a macrolide compound produced by the bacterium Streptomyces hygroscopicus that is used in medicine to prevent organ transplant rejection and to treat lymphangioleiomyomatosis.[5][6] It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It inhibits activation of T cells and B cells by reducing the production of interleukin-2 (IL-2). Sirolimus is also used as a coating for coronary stents.

Sirolimus was isolated for the first time in 1972 by Suren Sehgal and colleagues from samples of Streptomyces hygroscopicus found on Easter Island.[7][8] The compound was originally named rapamycin after the native name of the island, Rapa Nui.[6] 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).

Medical uses

Sirolimus is indicated for the prevention of organ transplant rejection and for the treatment of lymphangioleiomyomatosis (LAM).[5]

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 chronic renal 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.[9][10] 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.[11]

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 a 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.[12]

Lymphangioleiomyomatosis

On May 28, 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.[13] 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.[5]

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 effect 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.[13]

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.[13]

The safety of LAM treatment by sirolimus in patients younger than 18 years old has not been tested.[5]

Coronary stent coating

Further information: Drug-eluting stent

The antiproliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus-eluting stents when compared to bare-metal stents, resulting in fewer repeat procedures. A sirolimus-eluting coronary stent was marketed by Cordis, a division of Johnson & Johnson, under the tradename Cypher.[14] However, this kind of stent may also increase the risk of vascular thrombosis.[15]

Contraindications

Sirolimus is contraindicated in individuals with a known hypersensitivity to the drug.[5]

Adverse 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.[5]

The most common adverse reactions (≥20% occurrence, leading to a 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.[5]

The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant:[5]

System Adverse effects
Body as a Whole Sepsis, lymphocele, herpes zoster infection, herpes simplex infection
Cardiovascular Venous thromboembolism (pulmonary embolism and deep venous thrombosis), rapid heart rate
Digestive Stomatitis
Hematologic/Lymphatic Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia
Metabolic Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes
Musculoskeletal Bone necrosis
Respiratory Pneumonia, epistaxis
Skin Melanoma, squamous cell carcinoma, basal cell carcinoma
Urogenital Pyelonephritis, ovarian cysts, menstrual disorders (amenorrhea and menorrhagia)

Diabetes-like symptoms

While sirolimus inhibition of mTORC1 appears to mediate the drug's benefits, it also inhibits mTORC2, which results in diabetes-like symptoms. This includes decreased glucose tolerance and insensitivity to insulin.[16] Sirolimus treatment may additionally increase the risk of type 2 diabetes.[17] In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or analogs such as everolimus or temsirolimus.[18]

Lung toxicity

Lung toxicity is a serious complication associated with sirolimus therapy,[19][20][21][22][23][24][25] especially in the case of lung transplants.[26] 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.[27][28][29] The interstitial pneumonitis is not dose-dependent, but is more common in patients with underlying lung disease.[19][30]

Lowered effectiveness of immune system

There have been warnings about the use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections.[5][31]

Cancer risk

According to 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.[5]

Impaired wound healing

Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have a high body mass index (i.e., a BMI of ≥30 kg/m2).[5]

Interactions

Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump;[5] 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.[5]

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 cytokines receptor-dependent signal transduction mechanisms, via action on mTOR, and thereby blocks activation of T and B cells. Tacrolimus and cyclosporine inhibit the secretion of IL-2, by inhibiting calcineurin.[12]

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 (mechanistic (formerly mammalian) Target Of Rapamycin, rapamycin being another name for sirolimus) pathway by directly binding to mTOR Complex 1 (mTORC1).[12]

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.[12]

Pharmacokinetics

Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump.[5] It has an elimination half-life of 57–63 hours.[3]

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.[12] 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.[32][non-primary source needed]

Chemistry

Sirolimus is a natural product and macrocyclic lactone.[3]

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.[33] 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.[34]

Figure 1: Domain organization of PKS of rapamycin and biosynthetic intermediates
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.[35]

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.[33] 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.[36][37] 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.[38] 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.[33] 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.

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[39] or otherwise promote tumor regression in clinical trials.[40] Sirolimus seems to lower the cancer risk in some transplant patients.[41]

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.[42]

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.[43][44][45][46]

Tuberous sclerosis complex

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.[47]

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 majorly 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.[48]

Effects on longevity

Rapamycin was first shown to extend lifespan in eukaryotes in 2006 by Powers et al. who showed a dose-responsive effect of rapamycin on lifespan extension in yeast cells.[49][non-primary source needed] Building on this and other work, in a 2009 study, the lifespans of mice fed rapamycin were increased between 28 and 38% from the beginning of treatment, or 9 to 14% in total increased maximum lifespan. Of particular note, the treatment began in mice aged 20 months, the equivalent of 60 human years.[50][non-primary source needed] Rapamycin has subsequently been shown to extend mouse lifespan in several separate experiments,[51][52] and is now being tested for this purpose in nonhuman primates (the marmoset monkey),[53] and with an ongoing attempt to organize a study in dogs.[54] The Dog Aging Project is funded by pet owners.[55]

Because rapamycin at high doses can suppress the immune system, people taking rapamycin for transplant or cancer therapy are warned of potentially greater susceptibility to dangerous infections.[5] Yet paradoxically, rapamycin was shown to enhance the ability of aging mice to mount an immune response to a vaccine against tuberculosis.

A similar immunological "rejuvenating" effect was later documented in elderly humans administered a rapamycin analog prior to influenza vaccination), further fueling optimism for the potential of mTOR as a target for anti-aging drugs for humans.

It is not known whether rapamycin will have similar lifespan-lengthening effects in humans, and the authors of one study caution that the drug should not be used by the general population for this purpose.[56][unreliable medical source] It is hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity.

It is believed that this is achieved by limiting the essential amino acid leucine, a potent activator of mTOR.

The administration of leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway.[57][non-primary source needed]

According to the free radical theory of aging,[58] reactive oxygen species cause damage of mitochondrial proteins and decrease of ATP production. Subsequently, via ATP sensitive AMPK, the mTOR pathway is inhibited and ATP consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the ribosome.[59] Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration.[60] These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates glycolysis[60] and removal of dysfunctional cellular components via autophagy.[58]

Tuberous sclerosis in mice, with possible relevance to autism

In a study of sirolimus as a treatment for tuberous sclerosis, researchers observed improvements in TSC symptoms which overlap with autism. The researchers discovered that sirolimus regulates one of the same proteins the TSC gene does, but in different parts of the body. They decided to treat mice three to six months old (adulthood in mice lifespans); this increased the TSC mice's intellect to about that of normal mice in as little as three days.[61]

Alzheimer's in mice

Sirolimus reduced brain lesions and prevented the decline of performance in the water maze in mice with a mouse model of Alzheimer's.[62] Recent studies have observed a protective effect against Alzheimer's Disease in preventing cognitive deficits and reducing amyloid-β levels in mouse models. [63]

Muscular dystrophy in mice

Researchers at Washington University School of Medicine in St. Louis observed that administration of nanoparticles coated in sirolimus increases grip strength by 30% and significantly increases cardiac function in mice. The nanoparticles consist of perfluorocarbon cores and are 200 nm in diameter. The nanoparticles accumulate in areas of inflammation, in this case muscle, where they release a small dose of sirolimus. This suppresses the immune system and promotes autophagy.[64]

Systemic lupus erythematosus in mice and humans

Sirolimus improves disease activity and dependence on prednisone in systemic lupus erythematosus (SLE) patients resistant or intolerant to immunosuppressant medications. Sirolimus acts through blocking the activation of its molecular target, the mechanistic target of rapamycin complex 1 (mTORC1). The activation of mTORC1, which is associated with suppression of mTORC2, results in the expansion of proinflammatory CD4-CD8- double-negative (DN) T lymphocytes. These DN T cells produce inflammatory cytokines, interleukin-4 (IL-4) and interleukin-17, and they exhibit predisposition to proinflammatory cell death through necrosis. Increased IL-4 production is responsible for activation of autoantibody-producing B lymphocytes in SLE.[65][66][67][68][69] Sirolimus also blocks disease in lupus-prone mice by reversing the activation of mTORC1.[70] Prospective clinical trial in SLE patients with sirolimus is ongoing.

Other afflictions

Studies in vitro, in mice, and in humans suggest sirolimus inhibits HIV replication through different mechanisms, including downregulation of the coreceptor CCR5[71] and the induction of autophagy.[72]

In addition, sirolimus is currently being assessed as a therapeutic option for autosomal-dominant polycystic kidney disease (ADPKD). Case reports indicate sirolimus can reduce kidney volume and delay the loss of renal function in patients with ADPKD.[73]

Sirolimus has also been used in preliminary research to combat progeria, a rare disorder that causes individuals to age at an exceedingly rapid pace, leading to an extremely compromised cell-damage repair capacity and typically resulting in death in the early teenage years due to causes which are generally associated with old age such as heart disease or stroke.[74]

Applications in biology research

Rapamycin is used in biology research as an agent for chemically induced dimerization.[75] 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.

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