A mass of studies have revealed that mTOR is a serine/threonine protein kinase closely related to the occurrence of A mass of studies have revealed that mTOR is a serine/threonine protein kinase closely related to the occurrence of various human diseases. Inhibiting the mTOR signaling pathway can effectively block the abnormal signal transduction of different growth factors, thereby preventing diseases from occurring or deteriorating. mTOR inhibitors have gone through three generations of renewal to increase their performance. This blog briefly summarizes the research progress in mTOR inhibitors.
mTOR inhibitors are roughly divided into three categories: antibiotic allosteric mTOR inhibitors (first-generation), ATP-competitive mTOR inhibitors (second generation), and other novel mTOR inhibitors (third generation).
First Generation
First-generation mTOR inhibitors generally refer to antibiotic allosteric mTOR inhibitors, including rapamycin and its derivatives (rapalogs).
Considering its poor water solubility, stability, and bioavailability, rapamycin should go through a series of structural modifications so as to improve its pharmacokinetics. The earliest and relatively mature modification site is c-42, which is also considered the best choice without weakening the biological activity of the whole compound.
Rapamycin doesn’t directly inhibit mTOR activity, but it can be combined with FK506-binding protein 12 (FKBP12) to form the FKBp2-Rapamycin complex, which then binds to the FRB domain of mTOR. During the process, rapamycin is embedded in the cavity formed by FKBP12 and the FRB domain of mTOR. The conformation of mTOR is later altered to inhibit mTORC1 activity in an allosteric manner. Since the FRB domain is unique to mTOR, rapamycin has excellent selectivity for mTOR and is effective in the nanomolar range.
Rapamycin derivatives have a similar mechanism of action to themselves. Some examples are listed below. Temsirolimus (CCI-779) is the first derivative of rapamycin developed by Wyeth. It is transformed into rapamycin by CYP3A4 and is more water-soluble and stable than rapamycin. However, the esters are easily degraded by oral administration and are only used by intravenous administration. Everolimus (RAD001) is an oral rapamycin derivative from Novartis with improved water solubility and stability as well and is effective in the treatment of a wide range of tumors. Ridaforolimus (AP23573, MK-8669), also known as Deforolimus, is developed by Merck and ARIAD. Umirolimus (TRM-986) is highly lipophilic and has shown effective activity in immunosuppression and anti-proliferation. Zotarolimus (ABT-578) has a tetrazole substitutor at the C-42 position and exhibits an (S) -configuration, which is contrary to other rapamycin derivatives.
Second Generation
The second generation of mTOR inhibitors mainly include ATP-competitive inhibitors that bind to ATP-binding sites in the mTOR kinase domain. Structurally, it can be divided into many categories:
(1) Pyrazolepyrimidines
Pyrazopyrimidine is one of the common main structure of kinase inhibitors. Researchers screen the library of compounds and produce two 4-amino pyrazolpyrimidine parent nuclear compounds S1 and S2 which are further Pyrazopyrimidine is one of the common main structure of kinase inhibitors. Researchers screen the library of compounds and produce two 4-amino pyrazolpyrimidine parent nuclear compounds S1 and S2 which are further modified to obtain PP242 and PP30 displaying strong selectivity and activity against mTOR. PP242 can inhibit the kinase activities of PKC, RET, and JAK2 to a certain extent, which may be attributed to its structural similarity to the adenine of ATP. PP487 and PP121 have some tyrosine kinase inhibitory activity against Abl, Hck, Src, VEGFR2, and PDGFR as well.
(2) Imidazopyrimidines
Compound 21, discovered through high-throughput screening, is a moderately potent mTOR inhibitor with a Ki value of 72nM. By introducing substituted morpholine into the hinge binding region and replacing aminopyrimidine with phenylurea on the pyrimidine skeleton, researchers successfully improve the potency of mTOR and selectivity to PI3K. Statistics indicate that compound 22 (mTOR Ki=9nM) is 8 times more potent against mTOR than compound 21, 21 times more selective than PI3Kα, and 17 times more selective than PI3Kδ.
(3) Pyridinepyrimidines
Racemate 26 obtained based on high-throughput screening showed certain mTOR inhibitory activity. Further studies on the structure-activity relationship find that KU0063794 could inhibit both mTORC1 and mTORC2 with IC50 of 10nM, showing high selectivity. It also showed no inhibitory activity against 76 other protein kinases and 7 lipid kinases (PI3Kα and PI3Kβ I, PI3K-B II, VPS34 III, SPHK-1, SPHK-2, and choline kinases) at 10μM concentration. However, the compound’s relatively low water solubility (2.4μM) and relatively high hERG toxicity (IC50=8.3μM) limit further clinical development. In order to improve water solubility, several strategies such as introducing basic groups and reducing lipophilicity are tried. AZD8055 is an orally bioavailable, potent, and selective mTOR kinase inhibitor that is approximately 1000 times more selective than the PI3K subtype or related PIKK family members. AZD8055 has good tumor cell proliferation inhibition activity in vitro and in vivo, and is currently in phase I clinical trials. However, oral bioavailability in rats is low, only 12%. In order to improve the pharmacokinetic properties, further structure-activity relationship studies help obtain AZD2014 with water solubility increased (>600μM), hERG toxicity significantly decreased (IC50=47.5μM), and oral bioavailability of rats increased to 40%. Unfortunately, Astrazeneca discontinued AZD2014 in a Phase II study in 2018.
Compound 30 is a novel dual inhibitor of PI3K/mTOR, with more than 10 times higher selectivity to mTOR than PI3K family, and high anti-proliferation ability against breast cancer cell lines McF-7, MDA-MB-231, and MDA-MB-468. Changing the properties of the substituted group on compound 30 terminal phenylurea group from hydrogen bond donor to hydrogen bond receptor can promote the additional interaction with PI3Kα protein and enhance the affinity for PI3Kα. Compound 31 inhibited the proliferation of MDC7 cells in a dose-dependent manner with an IC50 of about 170nM.
(4) Thiopheno pyrimidines
GDC-0941 is a PI3K inhibitor, and also has a certain inhibitory effect on mTOR, with an IC50 value of 580nM against mTOR and 3nM against PI3Kα. More studies find that 2-aminopyrimidine instead of indazole fragment could improve tGDC-0941 is a PI3K inhibitor, and also has a certain inhibitory effect on mTOR, with an IC50 value of 580nM against mTOR and 3nM against PI3Kα. More studies find that 2-aminopyrimidine instead of indazole fragment could improve the inhibitory activity of mTOR, the introduction of methyl in thiophenazine nuclei could reduce the in vivo scavenging rate, and lactate amide instead of sulfonamide could increase the thermodynamic solubility of the compound at neutral pH. GDC-0980 is a dual PI3K/mTOR inhibitor with excellent proliferation inhibition on breast cancer, pancreatic cancer, NSCLC, and colon cancer cell lines. Compound 34, obtained by introducing cyclomorpholine and phenylurea into the thiophenol parent nuclei, has the strongest mTOR inhibition activity in the series, and its selectivity to mTOR is more than 400 times that of PI3Kα. GNE-493, another compound obtained by optimization based on GDC-0941, has good pharmacodynamic and pharmacokinetic properties in vivo, and has better selectivity compared to 130 kinases. GNE-477 is obtained by introducing methyl into GDC-0941 thiophene ring to break the flatness, and its clearance rate gets improved in vivo.
(5) Triazine
PKI-587 is a novel and effective PI3K/mTOR dual inhibitor with a triazine skeleton. The presence of three nitrogen atoms in the triazine skeleton increases the molecular polarity and leads to a lower cLogP. The IC50 values of PKI-587 against mTOR and PI3Kα are 1.6nM and 0.4nM respectively. PKI-587 exhibits significant inhibitory effect on MDA-361 and PC3-mm2 cells, and also shows good efficacy in vivo. After introducing 2-oxy-triazine structure into this class of inhibitors, and the resulting compound 38 shows significant proliferation inhibition on MDA-MB-361 and PC3 tumor cell lines with IC50 of 3 and 9nM respectively, showing high solubility and great stability in rats, nude mice, mice, and human microsomes. PKI-179 is another compound modified based on PKI-587. In order to increase cLogp value, one morpholine ring in PKI-587 is replaced by bridging morpholine ring, while the other morpholine ring is retained to form a key hydrogen bond interaction with Val851 in the hinge region. In addition, by removing the amide part, The IC50 of PKI-179 against mTOR and PI3Kα is 0.42nM and 8nM respectively. PKI-179 has significant inhibitory activity against MDA-361 and PC3mm2 cell lines. The compound is stable in nude mice and rats, but moderate in human (t1/2=14min). Metabolite identification shows that the cyclomorpholine group is the main metabolic site. Metabolite 40 also had certain mTOR inhibitory activity with IC50 of 0.8nM and IC50 of 4nM against PI3Kα.
(6) Benzodiazepines and quinolines
Firstly, the lead compound 50 is obtained by medium flux screening of mTORC1, and then Torin 1 is obtained by introducing hexane lactamide to form a new tricyclic skeleton and structural modification. Torin1 inhibits the phosphorylation of mTORC1 and mTORC2 at nanomolar concentration, and Torin1’s selectivity to mTOR is 900 times higher than PI3K. However, its poor stability and low oral bioavailability limit further in vivo studies. Torin 1 is modified to remove metabolic site groups, reduce molecular weight, and further improve water solubility to obtain Torin 2 with improved stability. For the analysis of Torin 2 binding mode with mTOR, α,β-unsaturated lactam structure is very important, and its condensation with quinoline ring c-3 and C-4 position limits the conformation of m-trifluoromethyl benzene ring. However, as Michael receptor, α,β -unsaturated lactam can be easily captured in vivo. This results in a short clearance half-life of Torin 2. The 6-member lactam ring is opened and intramolecular hydrogen bonds are introduced to simulate its bioactive conformation. The quinoline derivative designed is an effective mTOR inhibitor with an IC50 of 14nM and strong cell activity.
NSC781406 is a novel and effective PI3K/mTOR dual inhibitor, with an average GI50 of 65nM in 60 cancer cell lines, among which the GI50 of 4 cancer cell lines is less than 10nM. In addition, NSC781406 also shows effective tumor growth inhibition in hepatocellular carcinoma cell xenotransplantation model, better than sorafenib. GSK1059615 is a PI3K inhibitor entering the clinic. The eutectic structure indicates the interaction between thiazolidinedione and the catalytic lysine (Lys833) in the ATP binding pocket of PI3Kγ, but the cavity can also accommodate a larger group. Based on the modification of GSK1059615, GSK2126458 is found to be an mTOR/PI3K dual inhibitor with a Ki value of 0.18nM for mTORC1 and 0.3nM for mTORC2. GSK2126458 has low plasma clearance and good oral bioavailability. It also shows excellent activity and tolerance in vivo.
(7) Imidazoline-quinolones
The imidazo [4, 5-C] quinoline framework mimics the adenine portion of ATP in a variety of binding modes to generate hydrogen bond interactions with the hinge region of kinases. Nvp-bez235 is an oral mTOR/PI3K dual inhibitor developed by Novartis with an IC50 of 20.7nM for mTOR and IC50 values of 4nM, 75nM, 7nM and 5nM for PI3Kα, β, δ and γ. Nvp-bgt226 is another oral mTOR/PI3K dual inhibitor developed by Novartis, which has certain cytotoxic activity and has been studied in liver cancer, head and neck cancer, pancreatic cancer, and non-small cell lung cancer. LY3023414 is an oral mTOR/PI3K dual inhibitor developed by Eli Lilly. The IC50 for mTOR is 165nM, and the IC50 values for PI3Kα, β, δ and γ are 6.07nm, 77.6nM, 38nM and 23.8nm respectively. Compared with other PI3K/mTOR inhibitors, this compound has good solubility and dissolution properties that facilitate absorption, so it has high bioavailability.
(8) Others
PI-103, the first recognized mTOR/PI3K dual inhibitor, is obtained by Astella, a Japanese pharmaceutical company, through high-throughput screening and structural optimization. The IC50 is 20nM for mTOR and 3nM for PI3K. PI-103 has a good inhibitory effect on some tumor cells, but has not entered the clinic due to poor drug properties. High-throughput screening of mTOR activity results in an inhibitor containing a new skeleton, and further optimization results in the best compound in the series XL388, with moderate bioavailability, good pharmacokinetics, and oral exposure. PKI-402 has the parent nucleus structure of triazoprimidine, and its IC50 values against mTOR and PI3Kα are 1.7nM and 1.4nM respectively. In vivo efficacy study of PKI-402 against MDA-361 cell xenograft tumor shows that 100mg/kg iv induces tumor regression, and tumor does not regrow within 70 days.
PF-04691502 can effectively inhibit the PI3K/mTOR signaling pathway and inhibit tumor cell proliferation, showing strong anti-tumor activity in SKOV3 ovarian cancer xenotransplantation model and four NSCLC xenotransplantation models (NCI-H460, A549, NCI-H1650, and NCI-H1975). VS-5584 significantly regulates the PI3K/mTOR pathway, inhibits the phosphorylation of downstream substrates of PI3K and MTORC1/2, and shows high anti-proliferation activity in broad-spectrum cancer cells and effectiveness against many rapamycin resistant cell lines. GDC-0084 is a potent purine-based PI3K/mTOR inhibitor with a Ki value of 70nM against mTOR and 2nM against PI3Kα, which can penetrate the blood-brain barrier and inhibit tumor growth in U87 xenograft model with good tolerability. OSI-027 has an IC50 of 4nM against mTOR and has a broad spectrum of antitumor activities against mTORC1 and mTORC2 in different cancer cell lines (BT-474, IGR-OV1, and MDA-MB-231). Significant tumor growth inhibition is shown in several models including breast, colon, lung, prostate, lymphoma, and head/neck cancers and is well tolerated, with less than 10% weight loss observed during treatment.
Third Generation
The third-generation mTOR inhibitor rapalink-1 is derived from integrating rapamycin with mTOR kinase inhibitor MLN018 into the same molecule. It acts on mTOR by binding to the FRB domain of FKBP12, while the linked small molecule inhibitor MLN018 acts on the mTOR kinase domain.
Conclusion
In addition to the first-generation, second-generation, and third-generation mTOR inhibitors described above, some natural products have also been applied to either directly or indirectly inhibit mTOR and mTOR signaling pathways, such as Curcumin, EGCG, Resveratrol, and Sulforaphane.
It is easier to synthesize small-molecule mTOR inhibitors targeting ATP-binding sites with higher inhibition It is easier to synthesize small-molecule mTOR inhibitors targeting ATP-binding sites with higher inhibition effectiveness. Therefore, small molecule mTOR inhibitors are likely to become the future research frontier. Owing to the drug resistance mechanism of the second-generation mTOR inhibitors, the R&D of the third generation has been the focus of pharmacologists and pharmaceutical chemists. In the near future, more breakthroughs are to be made with the concerted efforts of all parties.
References:
1. Yifan Chen, Xiaoping Zhou. Researchprogress of mTOR inhibitors. Eur.J. Med. Chem. 2020, 208, 112820.
2. Tian Xua, Dejuan Sun, et al. Targeting mTORfor fighting diseases: A revisited review of mTOR inhibitors. Eur. J. Med. Chem. 2020, 199, 112391.
Related Targets:
| Targets | Description |
| mTOR | The mechanistic target of rapamycin (mTOR). mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases. |
| PKC | Protein kinase C (PKC) family members regulate numerous cellular responses including gene expression, protein secretion, cell proliferation, and the inflammatory response. |
| PI3K | PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. |
| JAK | Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. |
Related Products:
| Targets | Name | CAS | Synonyms | Description |
| mTOR | Temsirolimus | 162635-04-3 | CCI779; CCI-779; CCI 779; Temsirolimus; US brand name: Torisel. | Temsirolimus potently inhibits mTOR kinase activity with IC50 of 1. |
| mTOR | Everolimus | 159351-69-6 | RAD-001; RAD001; RAD 001; Afinitor; Certican; Zortress; RAD001; SDZ-RAD; 40-O-(2-Hydroxyethyl)rapamycin; 42-O-(2-Hydroxy)ethyl Rapamycin | Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) with an immunosuppressive activity which is comparable to that of rapamycin. |
| mTOR | Ridaforolimus | 572924-54-0 | AP23573; AP 23573; AP-23573; MK8669; MK 8669; MK-8669; Deforolimus, Ridaforolimus | Ridaforolimus is a small molecule and non-prodrug analogue of the lipophilic macrolide antibiotic rapamycin with potential antitumor activity. |
| mTOR | Umirolimus | 851536-75-9 | Biolimus; Biolimus A9; TRM 986; 42-O-(2-Ethoxyethyl)rapamycin | A semi-synthetic macrocyclic lactone prepared from rapamycin by selective alkylation of the 42-hydroxy group. |
| mTOR | Zotarolimus | 221877-54-9 | A-179578; A 179578; A179578; ABT-578; ABT578; ABT 578 | Zotarolimus (INN, codenamed ABT-578) is an immunosuppressant. |
| mTOR | PP242 | 1092351-67-1 | PP242; PP 242; PP-242; Torkinib. | PP242 is a novel potent and selective mTOR inhibitor with an IC50 of 8 nM. |
| mTOR | PP121 | 1092788-83-4 | PP121; PP 121; PP-121 | PP121 is a multitargeted dual receptor tyrosine kinases inhibitor. |
| mTOR | Ku-0063794 | 938440-64-3 | KU0063794; KU-0063794; KU 0063794; Ku0063794; Ku 0063794; Ku-0063794; KU63794; KU 63794; KU-63794; [5-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-4-morpholin-4-ylpyrido[2,3-d]pyrimidin-7-yl]-2-methoxyphenyl]methanol | KU-0063794 is an inhibitor of both mTORC1 and mTORC2 with an IC50 of approximately 10 nM, but does not suppress the activity of 76 other protein kinases or seven lipid kinases, including Class 1 PI3Ks (phosphoinositide 3-kinases) at 1000-fold higher concentrations. |
| mTOR | AZD-8055 | 1009298-09-2 | AZD8055; AZD-8055; AZD 8055. | AZD-8055 is an inhibitor of the mammalian target of rapamycin (mTOR) with potential antineoplastic activity. |
| mTOR | AZD-2014 | 1009298-59-2 | AZD2014, AZD-2014, AZD 2014, Vistusertib | AZD2014 is an orally bioavailable inhibitor of the mammalian target of rapamycin (mTOR) with potential antineoplastic activity. |
| PI3K | GDC0941 | 957054-30-7 | 4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine; GDC-0941; GDC 0941; GDC0941; RG7321; RG-7321; RG 7321; GNE0941; GNE-0941; GNE 0941; Pictrelisib; Pictilisib | GDC-0941 is a potent pan inhibitor of class I catalytic subunits of PI3K that inhibits p110α, β, δ, and γ with IC50 values of 3, 33, 3, and 75 nM. |
| PI3K/mTOR | Apitolisib | 1032754-93-0 | GDC-0980; GDC0980; GDC 0980; RG7422; RG-7422; RG 7422; GNE 390; GNE390; GNE-390; Apitolisib | Apitolisib, also known as GDC-0980 and RG7422 |
| PI3K/mTOR | GNE-493 | 1033735-94-2 | GNE493; GNE-493; GNE 493 | GNE-493 is a potent, selective, and orally available dual pan-PI3K/mTOR inhibitor with IC50s of 3. |
| PI3K/mTOR | GNE-477 | 1032754-81-6 | GNE-477, GNE477, GNE 477 | GNE-477 is a potent and efficacious dual PI3K/mTOR inhibitor with IC50 of 4 nM for PI3Kα and Kiapp of 21 nM for mTOR. |
| PI3K/mTOR | Gedatolisib (PF-05212384, PKI-587) | 1197160-78-3 | PKI587; PKI-587; PKI 587; PF05212384; PF-05212384; PF 05212384; PF5212384; PF-5212384; PF 5212384; Gedatolisib. | Gedatolisib (PF-05212384, PKI-587) is a highly potent dual inhibitor of PI3Kα, PI3Kγ and mTOR with IC50 of 0. |
| PI3K/mTOR | PKI-179 | 1197160-28-3 | PKI-179; PKI 179; PKI179 | PKI-179 is asecond generation, small-molecule mimetic of ATP that targets the mammalian target of rapamycin (mTOR) with potential antineoplastic activity. |
| mTOR | Torin 1 | 1222998-36-8 | Torin-1; Torin1; Torin 1. | Torin1 inhibits phosphorylation of mTORC1 and mTORC2 substrates in cells at concentrations of 2 and 10 nM, respectively. |
| mTOR | Torin 2 | 1223001-51-1 | Torin-2; Torin2; Torin 2; 9-(6-aminopyridin-3-yl)-1-[3-(trifluoromethyl)phenyl]benzo[h][1,6]naphthyridin-2-one | Torin 2 inhibits ATM/ATR/DNA-PK with EC50 of 28 nM/35 nM/118 nM, in PC3 cell lines respectively. |
| PI3K/mTOR | NSC781406 | 1676893-24-5 | NSC-781406; NSC 781406; NSC781406; 2,4-difluoro-N-[2-methoxy-5-[4-[3-(4-methylsulfonylpiperazin-1-yl)prop-1-ynyl]quinolin-6-yl]pyridin-3-yl]benzenesulfonamide; CHEMBL3763244; BDBM50145412 | NSC781406 demonstrates potent PI3K inhibition (PI3Kα IC50=2. |
| PI3K | GSK1059615 | 958852-01-2 | GSK-1059615; GSK 1059615; GSK1059615. | GSK1059615 is a dual inhibitor of PI3Kα/β/δ/γ (reversible) and mTOR with IC50 of 0. |
| PI3K/mTOR | Omipalisib | 1086062-66-9 | GSK-2126458; GSK2126458; GSK 2126458; Omipalisib | Omipalisib, also known as GSK2126458, is asmall-molecule pyridylsulfonamide inhibitor of phosphatidylinositol 3-kinase (PI3K) with potential antineoplastic activity. |
| PI3K/mTOR | Dactolisib | 915019-65-7 | BEZ235; BEZ-235; BEZ 235; NVPBEZ235; NVP-BEZ235; NVP-BEZ-235; NVP-BEZ 235; Dactolisib. | Dactolisib, also known as BEZ235, is an orally bioavailable phosphatidylinositol 3-kinase (PI3K) inhibitor with potential antineoplastic activity. |
| PI3K/mTOR | NVP-BGT226 | 1245537-68-1 | BGT226 (NVP-BGT226); BGT 226 (NVP-BGT226); BGT-226 (NVP-BGT226) | BGT226 (NVP-BGT226) is a novel class I PI3K/mTOR inhibitor for PI3Kα/β/γ with IC50 of 4 nM/63 nM/38 nM. |
| PI3K/mTOR | LY-3023414 | 1386874-06-1 | LY3023414; UNII-C88817F47Y; LY-3023414; C88817F47Y; GTPL8918; 8-[5-(2-hydroxypropan-2-yl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methylimidazo[4,5-c]quinolin-2-one | LY3023414, a quinoline derivative, has been found to be a PI3Kα and mTOR inhibitor that could influence cell proliferation and cycle of tumor cells. |
| PI3K/mTOR | PI-103 | 371935-74-9 | 3-(4-morpholinopyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl)phenol; PI103; PI-103; PI 103 | PI-103 is a potent, cell-permeable, ATP-competitive inhibitor of phosphatidylinositol 3-kinase (PI3K) family members with selectivity toward DNA-PK, PI3K (p110α), and mTOR. |
| PI3K/mTOR | PKI-402 | 1173204-81-3 | PKI-402; PKI 402; PKI402. | PKI-402 is a selective, reversible, ATP-competitive, equipotent inhibitor of class I phosphatidylinositol 3-kinases (PI3K), including PI3K-alpha mutants, and mammalian target of rapamycin (mTOR |
| PI3K/mTOR | PF-04691502 | 1013101-36-4 | PF04691502; PF 04691502; PF-04691502; PF4691502; PF 4691502; PF-4691502; 2-amino-8-((1R,4R)-4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one | PF-04691502 is an agent targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. |
| PI3K/mTOR | VS-5584 | 1246560-33-7 | VS5584; VS 5584; VS5584; SB2343; SB2343; SB 2343. | VS-5584 is a pan-PI3K/mTOR kinase inhibitor with IC50s of 16 nM, 68 nM, 42 nM, 25 nM, and 37 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ and mTOR, respectively. |
| PI3K/mTOR | GDC-0084 | 1382979-44-3 | RG7666; RG-7666; RG 7666; GDC-0084; GDC0084; GDC 0084; 5-(6,6-dimethyl-4-morpholin-4-yl-8,9-dihydropurino[8,9-c][1,4]oxazin-2-yl)pyrimidin-2-amine | GDC-0084, a PI3K inhibitor, has been found to have probable antineoplastic effect and could pass blood-brain barrier with favourable penetration. |
| mTOR | OSI-027 | 936890-98-1 | OSI-027; OSI 027; OSI027 | mTOR kinase inhibitor OSI-027 is an orally bioavailable mammalian target of rapamycin (mTOR) kinase inhibitor with potential antineoplastic activity. |
| mTOR | Curcumin | 458-37-7 | Curcumin; Diferuloylmethane; Turmeric Yellow; curcumin I; C.I. 75300; Natural Yellow 3; NSC32982; UNIIIT942ZTH98. | Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family (Zingiberaceae). |
| mTOR | Resveratrol | 501-36-0 | trans-Resveratrol; SRT-501; SRT 501; SRT501; RM1812; RM1812; RM 1812; RM-1812; CA1201; CA 1201; CA-1201; Resvida; Vineatrol 20M; trans-Resveratrol; Trans-resveratrol; 3,4′,5-Trihydroxystilbene; 3,4′,5-Stilbenetriol; 3,5,4′-Trihydroxystilbene | Resveratrol (also known as SRT-501) is a phytoalexin derived from grapes and other food products with antioxidant and potential chemopreventive activities. |
| mTOR | Sulforaphane | 4478-93-7 | 4-methylsulfinybutyl isothiocyanatel; Sulforafan; Sulforaphan; Sulphoraphane; (R)-sulforaphane; L-sulforaphane | Sulforaphaneis a naturally-occurring phytochemical belonging to the class of isothiocyanates. |