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- INK 128 (MLN0128)
INK 128 (MLN0128)
INK 128 (MLN0128) is a selective inhibitor of mTOR with IC50 value of 1 nM [3].
mTOR (mammalian target of rapamycin) is an evolutionarily conserved serine/threonine kinase which combined PI3K/AKT/mTOR pathway and plays an important role in regulating many fundamental features of cell growth and division [1].
INK 128 (MLN0128) is a potent mTOR inhibitor. When tested with human pancreatic cancer cells, INK-128 treatment inhibited cell growth and survival via inhibiting mTOR in a time- and concentration- dependent manner [2]. In HER2-positive breast cell lines, INK 128 treatment significantly delayed cell cycle and inhibited cell proliferation through inhibiting mTOR [1].
In a ZR-75-1 breast cancer xenograft model, INK128 treatment in a dose of 0.3mg/Kg/day significantly inhibited tumor growth. When combined with other standard targeted therapy or chemotherapy such as sorafenib, sutent and paclitaxel, enhanced anti-tumor growth activity was observed. INK128 is reported to have excellent physiochemical properties and is currently undergoing preclinical evaluation [3]. When tested with MDA-MB361 mouse model, administration of INK 128 showed a resistance after 20 days, and combined with lapatinib resulted in long-lasting tumor regression [1].
References:
[1].? Garcia-Garcia, C., et al., Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res, 2012. 18(9): p. 2603-12.
[2].? Lou, H.Z., et al., The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells. Biochem Biophys Res Commun, 2014. 450(2): p. 973-8.
[3].? Jessen K, et al. INK128 is a potent and selective TORC1/2 inhibitor with broad oral anti-tumor activity. AACR 2009 Molecular targets and cancer therapeutics meeting poster; Boston: 2009.
- 1. Catherine DeMarino, Maria Cowen, et al. "Cannabinoids Reduce Extracellular Vesicle Release from HIV-1 Infected Myeloid Cells and Inhibit Viral Transcription." Cells. 2022 Feb 18;11(4):723. PMID:35203372
- 2. JLing NXY, Kaczmarek A, et al. "mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress." Nat Metab. 2020 Jan;2(1):41-49. PMID:31993556
- 3. Matko Cancer, Hutter S, et al. "Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy." Cell Stem Cell. 2019 Nov 20. pii: S1934-5909(19)30426-6. PMID:31786016
- 4. Dong Q, Majumdar G, et al. "Insulin-induced de novo lipid synthesis occurs mainly via mTOR-dependent regulation of proteostasis of SREBP-1c." Mol Cell Biochem. 2019 Sep 20. PMID:31541353
- 5. Samluk L, Urbanska M, et al. "Cytosolic translational responses differ under conditions of severe short-term and long-term mitochondrial stress." Mol Biol Cell. 2019 Jul 15;30(15):1864-1877. PMID:31116686
- 6. Topf U, Suppanz I, et al. "Quantitative proteomics identifies redox switches for global translation modulation by mitochondrially produced reactive oxygen species." Nat Commun. 2018 Jan 22;9(1):324. PMID:29358734
- 7. Dite TA, Ling NXY, et al. "The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs." Nat Commun. 2017 Sep 18;8(1):571. PMID:28924239
- 8. Robert R. Redfield,Alonso Heredia,et al. "Treatment agents for inhibiting hiv and cancer in hiv infected patients." Google Patents.2016.
- 9. Heredia, Alonso, et al. "Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice." Proceedings of the National Academy of Sciences (2015): 201511144. PMID:26170311
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 309.33 |
| Cas No. | 1224844-38-5 |
| Formula | C15H15N7O |
| Synonyms | INK128; INK-128 |
| Solubility | insoluble in H2O; ≥15.45 mg/mL in DMSO; ≥2.7 mg/mL in EtOH with gentle warming |
| Chemical Name | 5-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1,3-benzoxazol-2-amine |
| SDF | Download SDF |
| Canonical SMILES | CC(C)N1C2=C(C(=N1)C3=CC4=C(C=C3)OC(=N4)N)C(=NC=N2)N |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Kinase experiment [1]: | |
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Kinase assays |
mTOR activity was assayed using LanthaScreen Kinase kit reagents. PI(3)K α, β, γ and δ activity were assayed using the PI(3)KHTRF assay kit. The concentration of INK 128 necessary to achieve inhibition of enzyme activity by 50% (IC50) was calculated using concentrations ranging from 20 μM to 0.1 nM (12-point curve). IC50 values were determined using a nonlinear regression model. |
| Cell experiment [2]: | |
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Cell lines |
PANC-1 cells |
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Preparation method |
The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
10 ~ 100 nM; 72 hrs |
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Applications |
INK 128 time- and dose-dependently inhibited the survival of PANC-1 cells, and significantly reduced the viability of PANC-1 cells at the concentrations of 10 ~ 100 nM. There was no significant viability decrease until 48 hrs after INK 128 treatment. |
| Animal experiment [3]: | |
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Animal models |
A ZR-75-1 breast cancer xenograft model |
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Dosage form |
0.3 mg/kg/day; p.o. |
|
Applications |
In a ZR-75-1 breast cancer xenograft model, INK 128 significantly inhibited tumor growth. The combination therapy of INK 128 and other standard targeted therapy or chemotherapy such as Sorafenib, Sutent and Paclitaxel enhanced anti-tumor growth activity. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, Shi EY, Stumpf CR, Christensen C, Bonham MJ, Wang S, Ren P, Martin M, Jessen K, Feldman ME, Weissman JS, Shokat KM, Rommel C, Ruggero D. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012 Feb 22;485(7396):55-61. [2]. Lou, H.Z., et al., The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells. Biochem Biophys Res Commun, 2014. 450(2): p. 973-8. [3]. Jessen K, et al. INK128 is a potent and selective TORC1/2 inhibitor with broad oral anti-tumor activity. AACR 2009 Molecular targets and cancer therapeutics meeting poster; Boston: 2009. |
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| Description | INK 128 (MLN0128) is a potent and selective inhibitor of mTOR with an IC50 value of 1 nM. | |||||
| Targets | mTOR | PI3Kα | PI3Kγ | PI3Kδ | PI3Kβ | |
| IC50 | 1 nM (Ki=1.4 nM) | 219 nM | 221 nM | 230 nM | 5293 nM | |
Quality Control & MSDS
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