mtorc1

mTORC1-IN-1 (T1), a rapamycin homologue (rapalog) and selective inhibitor of mTORC1, controls cell growth and metabolism, with implications in various diseases such as cancer. It interacts with mTORC1 by attaching to the FKBP12-FRB complex, evidencing a docking score of -11.6 kcal/mol [1].

Rapamycin (AY 22989) is a natural product of macrolides, an mTOR inhibitor with specificity (HEK293 cells: IC50=0.1 nM). Rapamycin has immunosuppressive activity and induces autophagy.

NV-5138 is a selective and orally active activator of brain mTORC1, with antidepressant effects.

Indoximod (Indoximod (NLG-8189)) is a methylated tryptophan with immune checkpoint inhibitory activity. Indoximod inhibits the enzyme indoleamine 2, 3-dioxygenase (IDO), which degrades the essential amino acid tryptophan, and may increase or maintain tryptophan levels important to T cell function. Tryptophan depletion is associated with immunosuppression involving T cell arrest and anergy.

NS1-IN-1 is a potent NS1 inhibitor.NS1-IN-1 displays antiviral activity by inhibiting mTORC1 activity in a TSC1-TSC2-dependent manner.NS1-IN-1 reduces the level of viral proteins and contributes to the reduction of viral replication.

TCS-PIM-1-4a (SMI-4a), a Pim inhibitor, blocks mTORC1 activity through activation of AMPK and kills a wide range of both myeloid and lymphoid cell lines (IC50=0.8-40 μM).

WYE-125132 (WYE-132 (WYE-125132)) is a highly potent, ATP-competitive mTOR inhibitor with IC50 of 0.19 nM; highly selective for mTOR versus PI3Ks or PI3K-related kinases hSMG1 and ATR.

Autogramin-1 potently inhibits autophagy induced by either mTORC1 inhibition (Rapamycin; IC50: 0.44 μM) or starvation (IC50: 0.17 μM).

WAY-600 is a potent, ATP-competitive and selective inhibitor of mTOR with IC50 of 9 nM; blocks mTORC1/P-S6K(T389) and mTORC2/P-AKT(S473) but not P-AKT(T308); selective for mTOR than PI3Kα (>100-fold) and PI3Kγ (>500-fold).

Cbz-B3A is a potent inhibitor of mTORC1 signalling, inhibits phosphorylation of eIF4E-binding protein 1 (4EBP1) and blocks translation by 68%.

mTOR inhibitor-3 is a selective mTOR inhibitor (Ki= 1.5 nM). mTOR inhibitor-3 inhibits mTORC1 and mTORC2 in cellular and in vivo experiments.

GDC-0349 (RG-7603) is a potent and selective ATP-competitive inhibitor of mTOR with Ki of 3.8 nM, 790-fold inhibitory effect against PI3Kα and other 266 kinases. Phase 1.

AZD8055 is an ATP-competitive mTOR inhibitor (IC50: 0.8 nM in MDA-MB-468 cells). It is ~1,000-fold selective for mTOR over all PI3K isoforms.

Dactolisib Tosylate (BEZ235 Tosylate) is a dual kinase inhibitor that targets PI3K and mTOR. dactolisib Tosylate exhibits IC50 values of 4, 75, 7, and 5 nM for PI3Kα, β, γ, and δ, respectively. dactolisib Tosylate inhibits mTORC1 and mTORC2.

Palomid 529 (SG 00529) has been used in trials studying the treatment of Age-Related Macular Degeneration.

Dactolisib (BEZ235) is an orally bioavailable inhibitor of PI3K and mTOR (IC50s: 4 nM/5 nM/7 nM/75 nM, and 20.7 nM for p110α/p110γ/p110δ/p110β and mTOR).

OSI-027 (ASP4786) is a selective and potent dual inhibitor of mTORC1 and mTORC2 with IC50 of 22 nM and 65 nM, and more than 100-fold selectivity observed for mTOR than PI3Kα, PI3Kβ, PI3Kγ or DNA-PK. Phase 1.

KU-0063794 is a potent and highly specific dual-mTOR inhibitor of mTORC1 and mTORC2.

Torin 1 is an effective inhibitor of mTORC1/2 with (IC50: 2 nM/10 nM); has 1000-fold selectivity for mTOR than PI3K.

WYE-354(IC50=5 nM) is an effective, selective and ATP-competitive mTOR inhibitor. It blocks mTORC2/P-AKT(S473) and mTORC1/P-S6K(T389), not P-AKT(T308). The selectivity for mTOR is higher than PI3Kα (>100-fold) and PI3Kγ (>500-fold).

XL388 is a highly effective, specifc, ATP-competitive inhibitor of mTOR ( IC50: 9.9 nM), 1000-fold selectivity than the closely related PI3K kinases.

Autogramin-2 (tert-butyl 2-(4-isopropoxybenzamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate) potently inhibits autophagy induced by either starvation with IC50 of 0.27 μM, and inhibits mTORC1 (Rapamycin; IC50:0.14 μM)

RMC-5552 is a potent and selective inhibitor of mTORC1. RMC-5552 inhibits phosphorylation of mTORC1 pS6K and p4EBP1 with IC50s of 0.14 nM and 0.48 nM, respectively. RMC-5552 has anti-cancer activity.

PQR620 is a novel potent and selective, brain penetrant inhibitor of mTORC1/2.

Thioether-cyclized helix B peptide, CHBP (TFA), is the trifluoroacetic (TFA) salt of CHBP. This form enhances metabolic stability and exhibits renoprotective effects by promoting autophagy, achieved through the inhibition of mTOR C1 and activation of mTOR C2 [1].

RMC-4627 is a selective mTORC1 inhibitor that activates 4EBP1 and inhibits tumor growth.

Thioether-cyclized helix B peptide (CHBP) enhances metabolic stability and exerts renoprotective effects by promoting autophagy through the inhibition of mTOR C1 and activation of mTOR C2 [1].

CC-115 is a inhibitor of mTOR/DNA-PK (IC50= 21/ 13 nM).

VS-5584 (SB2343) is a pan-PI3K/mTOR kinase inhibitor.

Voxtalisib (XL765) (SAR245409, XL765) is a dual inhibitor of mTOR/PI3K, mostly for p110γ with IC50 of 9 nM; also inhibits DNA-PK and mTOR. Phase 1/2.

Bimiralisib (PI3K-IN-2) is an orally bioavailable pan inhibitor of PI3K and inhibitor of the mTOR, with potential antineoplastic activity. PI3K-IN-2 inhibits the PI3K kinase isoforms alpha, beta, gamma and delta and, to a lesser extent, mTOR kinase, which may result in tumor cell apoptosis and growth inhibition in cells overexpressing PI3K/mTOR. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to both chemotherapy and radiotherapy.

PQR530 is a highly potent dual pan-PI3K/mTORC1/2 inhibitor. PQR530 inhibited protein kinase B (PKB, pSer473) and ribosomal protein S6 (pS6, pSer235/236) phosphorylation with IC50 values of 0.07 μM. It also showing antitumor activity.

Rheb inhibitor NR1 is a Rheb inhibitor and selective mTORC1 inhibitor.Rheb inhibitor NR1 inhibits the phosphorylation of T389pS6K1 and promotes the phosphorylation of S473pAKT.

Samotolisib (LY3023414) is an oral ATP competitive inhibitor of the class I PI3K isoforms, DNA-PK, and mTOR. Samotolisib (LY3023414) has been used in trials studying the treatment of Neoplasm, Solid Tumor, COLON CANCER, BREAST CANCER, and Advanced Cancer, among others.

NV-5440 is a novel cell penetrant, potent and selective class I glucose transporters (GLUT1) inhibitor, selectively inhibiting mTORC1

Timosaponin AIII (Timosaponin A3) induces autophagy in HeLa cells followed by apoptotic cell death (IC50: 10 μM). The Timosaponin AIII cellular response is mediated via inhibition of mTORC1 and induction of ER stress (IC50: 2.5 μM, BT474 cells; 6 μM, MDAMB231). The Timosaponin AIII pro-apoptotic response is selective for tumor cells over normal cells but autophagy is induced in both.

P7170 is an anti-cancer agent active as an mTORC1/C2 and activin receptor-like kinase 1 (ALK1) inhibitor.

CIDD-0067106 is a novel potent and selective antiproliferative agent, inhibiting the activity of the mtorc1 pathway

DCBCI0901 is an inhibitor of phosphatidylinositide 3-kinase (PI3K), raptor-mTOR (mTOR complex 1 or mTORC1) and rictor-mTOR (mTOR complex 2 or mTORC2) with potential antineoplastic activity.

CC214-2 is a potent dual inhibitor of mTORC1 and mTORC2, known for its ability to impede autophagy by modulating mammalian target of rapamycin (mTOR) signaling. With this capacity, CC214-2 shows promise in shortening the duration of tuberculosis (TB) [1].

Omipalisib (GSK2126458) is a small-molecule pyridylsulfonamide inhibitor of phosphatidylinositol 3-kinase (PI3K) with potential antineoplastic activity.

PI-103 is a potent, cell-permeable, ATP-competitive inhibitor of PI3K family members (IC50s: 2/3/3/15/30/23 nM for p110α/β/δ/γ, mTOR, and DNA-PK).

RORγ antagonist 1 (compound 22), a potent derivative of betulinic acid, acts as an antagonist to RORγ with a dissociation constant (K D) of 0.18 μM. It demonstrates anti-proliferative effects in the HPAF-II pancreatic cancer xenograft model, inhibits the RAS/MAPK and AKT/mTORC1 signaling pathways, and triggers caspase-dependent apoptosis in pancreatic cancer cells [1].

Gedatolisib (PF-05212384) is a highly effective dual inhibitor targeting the PI3Kα/γ (IC50: 0.4/5.4 nM)and mTOR (IC50: 1.6 nM) in the PI3K/mTOR signaling pathway.

BI-860585 is an inhibitor of Raptor-Mammalian Target of Rapamycin (mTOR) Complex 1 (mTOR Complex 1; mTORC1) and rictor-mTOR Complex 2 (mTOR Complex 2; mTORC2), with potential Anti-tumor activity.

YW3-56 is an inhibitor of protein arginine deiminase 2 (PAD2) and PAD4 (IC50s = 0.5-1 and 1-5 μM, respectively).1It inhibits the growth of U2OS osteosarcoma cells (IC50= ~2.5 μM) in a p53-dependent mannerviainduction of SESN2 and subsequent inhibition of mTORC1. YW3-56 (10 mg/kg) reduces tumor growth in an S-180 murine sarcoma tumor model. It also inhibits tumor growth in the 1883 MDA-MB-231 breast cancer bone metastasis mouse xenograft model.2 1.Wang, Y., Li, P., Wang, S., et al.Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activityThe Journal of Biological Chemisty287(31)25941-25952(2012) 2.Wang, S., Chen, X.A., Hu, J., et al.ATF4 gene network mediates cellular response to the anticancer PAD inhibitor YW3-56 in triple-negative breast cancer cellsMol. Cancer Ther.14(4)877-888(2015)

Vistusertib (AZD2014) is an orally bioavailable inhibitor of the mammalian target of rapamycin (mTOR) with potential antineoplastic activity.

Onatasertib (CC223) is an orally available mTOR inhibitor with potential antitumor activity. Onatasertib inhibits the activity of mTOR, which may result in the induction of tumor cell apoptosis and a decrease in tumor cell proliferation. Onatasertib is a potent mTOR kinase inhibitor (IC50: 16 nM), with >150-fold sensitivity than the related lipid kinase PI3Kα (IC50: 4 μM).

MT 63-78 is a specific and effective direct AMPK activator (EC50: 25 μM). MT 63-78 blocks prostate cancer growth by inhibiting the lipogenesis and mTORC1 pathways. MT 63-78 has antitumor effects. MT 63–78 also causes cell mitotic arrest and apoptosis.

NV-5138 hydrochloride is a leucine analog and is the first selective and orally active brain mTORC1 activator, binding to Sestrin2. NV-5138 hydrochloride can be used in the research of antidepressants [1] [2].