PI3K/mTOR Inhibitor-1, a Sulfonyl-Substituted Morpholinopyrimidines based analog, is a novel, potent, orally bioavailable dual PI3K/mTOR inhibitor with potential antitumor activity. and with IC50s of 20/376/204/46 nM and 186 nM for PI3Kα/PI3Kβ/PI3Kγ/PI3Kδ and mTOR, respectively. PI3K/mTOR Inhibitor-1 was identified as a potent dual PI3K/mTOR inhibitor whithc exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM) and mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphorylation (IC50 = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C4 sulfone chain and a fluorine on the C6 aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, PI3K/mTOR Inhibitor-1 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.
Physicochemical Properties
| Molecular Formula | C18H22FN5O3S |
| Molecular Weight | 407.462385654449 |
| Exact Mass | 407.142 |
| CAS # | 1949802-49-6 |
| PubChem CID | 121428416 |
| Appearance | Typically exists as solid at room temperature |
| LogP | 0.6 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 28 |
| Complexity | 671 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | C[C@H]1COCCN1C2=NC(=CC(=N2)C3(CC3)S(=O)(=O)C)C4=CN=C(C=C4F)N |
| InChi Key | LBIPJQHFIZPQHA-NSHDSACASA-N |
| InChi Code | InChI=1S/C18H22FN5O3S/c1-11-10-27-6-5-24(11)17-22-14(12-9-21-16(20)7-13(12)19)8-15(23-17)18(3-4-18)28(2,25)26/h7-9,11H,3-6,10H2,1-2H3,(H2,20,21)/t11-/m0/s1 |
| Chemical Name | 4-fluoro-5-[2-[(3S)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]pyridin-2-amine |
| Synonyms | PI3K/mTOR Inhibitor-1 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | Additionally, compound 26—PI3K/mTOR Inhibitor-1—shows strong suppression of AKT phosphorylation function (IC50=196 nM) [1]. On a panel of cancer cells, PI3K/mTOR Inhibitor-1 (0.046-10 µM, 72 hours) shows good antiproliferative effects. A431, A549, PC3, MDA-MB-361, SW480, ES-2, HT29, SK-OV-3, HCT116, G401, BT20, DLD1 HCC827, H1650, H460, Farage, H820, HCT15, H358, Colo-205, PC9, H1975, WSU-DLCL2, HT, A2780, SU-DHL-10, Toledo, SU-DHL-6, DB, and Pfeiffer cells are inhibited by the PI3K/mTOR inhibitor; the IC50 values are 0.188, 0.104, 0.063, 0.085, 0.534, 0.179, 0.163, 0.135, 0.308, 0.113, 0.729, 0.264, 0.287, 1.662, 0.611, 0.365, 0.104, 0.109, 0.237, 0.136, 0.14 5, 0.090, 0.251, 0. In that order, 215, 0.269, 0.111, 0.062, and 0.061 µM [1]. |
| ln Vivo | At a daily oral dose of 3.75 mg/kg for 27 days, PI3K/mTOR Inhibitor-1 (Compound 26) produced 54.4% tumor growth inhibition (TGI). The TGI was higher in the PI3K/mTOR Inhibitor-1 7.5 mg/kg group (72.9%). Following 27 days of therapy, every animal made it out alive, with the PI3K/mTOR Inhibitor-1, 7.5 mg/kg group experiencing a 15% reduction in body weight [1]. |
| Cell Assay |
Cell proliferation assay[1] Cell Types: U87-MG, A431, MCF-7, PC3, A549, MDA-MB-361, SW480, ES-2, HT29, SK-OV-3, HCT116, G401, BT20, DLD1 , HCC827, H1650, H460, Farage, H820, HCT15, H358, Colo-205, PC9, H1975, WSU-DLCL2, HT, A2780, SU-DHL-10, Toledo, SU-DHL-6, DB, Pfeiffer Cell Tested Concentrations:0.046-10 µM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibits HT-29 cell proliferation with IC50 of 0.163 µM. |
| Animal Protocol |
Animal/Disease Models: Balb/c nu/nu (nude) mice with PIK3CA P449T mutation HT-29 colorectal cancer xenograft mouse model [1] Doses: 3.75 and 7.5 mg/kg Route of Administration: Daily po (oral gavage), continuous 27-day Experimental Results: Tumor growth inhibition (TGI) was 54.4% and 72.9% at daily oral doses of 3.75 mg/kg and 7.5 mg/kg for 27 days, respectively. |
| References |
[1]. Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines. ACS Med Chem Lett. 2018 Jun 25;9(7):719-724. |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4542 mL | 12.2711 mL | 24.5423 mL | |
| 5 mM | 0.4908 mL | 2.4542 mL | 4.9085 mL | |
| 10 mM | 0.2454 mL | 1.2271 mL | 2.4542 mL |