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Purity: ≥98%
Bimiralisib (also known as PQR-309; PI3K-IN-2) is an orally bioavailable, brain-penetrant, and balanced pan-inhibitor of PI3K/mTOR (phosphoinositide-3-kinase/mammalian target of rapamycin) with IC50s of 33 nM, 451 nM, 661 nM, 708 nM and 89 nM for PI3Kα, PI3Kδ, PI3Kβ, PI3Kγ and mTOR, respectively. Bimiralisib is orally bioavailable, has the ability to cross the blood-brain barrier, and showed favorable pharmacokinetic parameters in mice, rats, and dogs. It also has the potential to have anti-cancer effects. In rat xenograft models and tumor cell lines, bimiralisib effectively inhibited proliferation. The treatment of brain tumors or CNS metastasis is just one of the many oncology uses for bimiralisib. Phase II clinical trials for bimiralisib are currently being conducted in patients with refractory lymphoma and advanced solid tumors.
| Targets |
PI3Kα (IC50 = 33 nM); PI3Kβ (IC50 = 661 nM); PI3Kδ (IC50 = 451 nM); PI3Kγ (IC50 = 708 nM); PI3Kα-H1047R (IC50 = 36 nM); PI3Kα-E545K (IC50 = 136 nM); PI3Kα-E542K (IC50 = 63 nM); Vps34 (IC50 = 6486 nM); mTOR (IC50 = 89 nM); DNA-PK (IC50 = 8567 nM); mTORC1; mTORC2
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| ln Vitro |
PQR309 exhibits in vitro activity in most of the tested lymphoma cell lines (increasing doses, 72 hours) with a median IC50 value of 233 nmol/L (95% CI, 174-324 nmol/L). A block in the G1 phase of the cell cycle, which affects only 2/7 cell lines, is the primary cause of the cell cycle arrest that is preventing proliferation. DLBCL, MCL, CLL, and SMZL are B-cell lymphoma cell lines that exhibit higher PQR309 activity than ALCL, a T-cell derived lymphoma. In lymphoma cell lines, PI3K/mTOR signaling is suppressed by PQR309. It has antilymphoma activity both alone and in combination in vitro and in vivo[1].
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| ln Vivo |
PQR309 is orally available, crosses the blood–brain barrier, and exhibits favorable pharmacokinetic characteristics in mice, rats, and dogs. When exposed to rat, dog, and human liver microsomes, it exhibits little clearance. However, mouse liver microsomes exhibit a quicker turnover of PQR309, with 40% of the compound being eliminated in less than 30 minutes. The half-life of PQR309 in female mice varied depending on the route of drug administration, with half-lives for oral administration being roughly 13–36 min and for intravenous administration being 9–10 min. PQR309 is orally available, crossesThe oral bioavailability of PQR309 is very good (>50%). When given PQR309 at a dose of 10 mg/kg po, male Beagle dogs displayed maximal drug plasma concentrations Cmax of 583 ng/mL (roughly 1.5 μM) after 60–90 min and a half-life of >7 h, translating to drug levels of about 0.38 μM (150 ng/mL) after 24 h. Male Beagle dogs' oral bioavailability was calculated to be 23%. The combined PK studies in the three models (male Beagle dog, female Sprague-Dawley rat, and female CD-1 mouse) show that PQR309 is rapidly absorbed and has a high oral bioavailability. In tumor cell lines (PC3 prostate cancer cells) and a rat xenograft model (PC3 xenograft model), PQR309 effectively inhibits proliferation[2].
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| Cell Assay |
Human tumor cell lines are seeded into 96-well microtiter plates and exposed to five (1/2 log serial) drug dilutions plus control, followed by 48 h (except for two controls of each cell line which are fixed with TCA (cell population at t =0 h [Tz]). TCA (10% final) fixation is used to end the assay. Using a sulforhodamine B staining procedure, the absorbance is measured at 515 nm to determine the cell density. The percentage growth at each drug concentration level is calculated using seven absorbance measurements. Calculated is the percentage of growth inhibition. Bimiralisib is serially diluted nine times, three times, and exposed for 72 hours to the NTRC Oncolines 44 cell lines. The signal ((luminescenceuntreated,t=72h-luminescencet=0)/2)+luminescencet=0) indicates the presence of 50% growth inhibition at a given concentration. IC50 calculations are performed using the data set integrated here. It is determined and calculated what the IC50 values are for the proliferation of A2058 or SKOV3 cells.
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| Animal Protocol |
Mice: Male NIH rats in good health are used. 24 hours after a whole-body irradiation with a -source (5 Gy, 60Co), 2×107 PC-3 cells are subcutaneously injected into the right flank of male nude rats at day 0 (D0) in 200 L of RPMI1640. Using the Vivo manager software, tumor-bearing rats are randomly divided into five groups of each eight animals on day 16 (mean volume of 33070 mm3 according to their individual tumor volume). To check for group homogeneity, analysis of variance is used. Daily administration of group 1, vehicle; group 2, compound 1 at 5 mg/kg; and group 3, bimiralisib at 10 mg/kg on days D17–D44 and D51–D57. Group 4: From D17 to D21, D24 to D28, D34 to D38, D41 to D4, and from D51 to D56, bimiralisib at 15 mg/kg. Group 5: On D17, D24, D31, and D38, receive one intravenous injection of 2.5 mg/kg Vinorelbine. On D87, rats are put to death for good. At least twice a week, weight is taken. Tumor length and width are measured with calipers twice a week, and the tumor volume is calculated.
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| References |
| Molecular Formula |
C17H20F3N7O2
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| Molecular Weight |
411.38
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| Exact Mass |
411.1631
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| Elemental Analysis |
C, 49.63; H, 4.90; F, 13.85; N, 23.83; O, 7.78
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| CAS # |
1225037-39-7
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| Related CAS # |
1820902-72-4 (HCl salt);1225037-39-7;
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| Appearance |
Solid powder
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| SMILES |
C1COCCN1C2=NC(=NC(=N2)C3=CN=C(C=C3C(F)(F)F)N)N4CCOCC4
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| InChi Key |
ADGGYDAFIHSYFI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H20F3N7O2/c18-17(19,20)12-9-13(21)22-10-11(12)14-23-15(26-1-5-28-6-2-26)25-16(24-14)27-3-7-29-8-4-27/h9-10H,1-8H2,(H2,21,22)
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| Chemical Name |
5-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.08 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.08 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4308 mL | 12.1542 mL | 24.3084 mL | |
| 5 mM | 0.4862 mL | 2.4308 mL | 4.8617 mL | |
| 10 mM | 0.2431 mL | 1.2154 mL | 2.4308 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02669511 | Completed | Drug: PQR309 | Primary Central Nervous System Lymphoma |
PIQUR Therapeutics AG | November 12, 2015 | Phase 1 Phase 2 |
| NCT02249429 | Completed | Drug: bimiralisib | Lymphoma, Malignant | PIQUR Therapeutics AG | May 2015 | Phase 2 |
 Efficacy model for antitumor activity of 1 (PQR309) in PC3 xenografts in nude rats.J Med Chem.2017 Sep 14;60(17):7524-7538. |
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 PK/PD assessment of1in mice, rats, and dogs: time course of1abundance in vivo.J Med Chem.2017 Sep 14;60(17):7524-7538. |
 Action of indicated compounds on cell cycle and PI3K and mTOR signaling. Cell proliferation in response to1represented as a waterfall blot.J Med Chem.2017 Sep 14;60(17):7524-7538. |
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