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PQR309 (Synonyms: PI3K-IN-2)

Catalog No.GC19300

PQR309 (PQR309) is a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor with IC50s of 33 nM, 451 nM, 661 nM, 708 nM and 89 nM for PI3Kα, PI3Kδ, PI3Kβ, PI3Kγ and mTOR, respectively. PQR309 is an mTORC1 and mTORC2 inhibitor.

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PQR309 Chemical Structure

Cas No.: 1225037-39-7

Size Price Stock Qty
2mg
$40.00
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5mg
$63.00
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10mg
$94.00
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50mg
$295.00
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100mg
$476.00
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500mg
$1,428.00
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1g
$2,285.00
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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Cell experiment [1]:

Cell lines

Human GBM cell lines (U87 and U251)

Preparation Method

5x103 cells were seeded in 96-well plate, and PQR309 was added into each well. Various concentrations of PQR309 (0, 1, 5, 10, 20, 50 and 100µM), as well as a certain concentration applied for different time-points (24, 48, 72 and 96h) were evaluated. Next, 10µL CCK-8 was added, and the cells were incubated for 1 h at 37℃.

Reaction Conditions

0, 1, 5, 10, 20, 50 and 100µM

Applications

PQR309 had a significant suppressive effect on U87 and U251 cells. The viability of the cells was significantly (P50values of PQR309 were 7.104 (95% CI, 5.6-8.5) and 11.986 (95% CI, 10.6-13.4) in U87 and U251 cells, respectively.

Animal experiment [2]:

Animal models

Healthy male nude NIH rats

Preparation Method

Rats were injected with 2×107 human PC3 prostate cancer cells into one flank and randomized after 16 days. From day 17, PQR309 was orally administered at 5mg/kg, 10mg/kg (both daily, QD), or 15mg/kg [5 consecutive days, 2 days off drug (QD×5, 2 days off)] for 28 days to match the timelines of regulatory toxicology studies.

Dosage form

5, 10, 15mg/kg, oral administration

Applications

Treatment with PQR309 led to significant tumor size reductions: tumor growth was inhibited dose-dependently (best T/C of 31-12%). PQR309 was best tolerated at 5mg/kg without significant body weight changes. At 10mg/kg, PQR309 caused a reduction of body weight, which accumulated to a reduction of 15% after 28 days of treatment. Similarly,15 mg/kg of PQR309 led to body weight loss after 5 days of treatment, which was reversible during the recovery period. After 28 days of drug exposure, animals with body weight loss fully recovered within a treatment-free period (days 45-50) without overt signs of tumor cell proliferation.

References:

[1]. Yang K, Tang XJ, et al. PI3K/mTORC1/2 inhibitor PQR309 inhibits proliferation and induces apoptosis in human glioblastoma cells. Oncol Rep. 2020;43(3):773-782.

[2]. Beaufils F, Cmiljanovic N, et al. 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology. J Med Chem. 2017;60(17):7524-7538.

Background

PQR309 is a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor with IC50s of 33nM, 451nM, 661nM, 708nM and 89nM for PI3Kα, PI3Kδ, PI3Kβ, PI3Kγ and mTOR, respectively[1][2].

PQR309 exerts an antitumor effect by inhibiting proliferation, inducing apoptosis, inducing G1 cell cycle arrest, and inhibiting invasion and migration in human glioma cells[3]. PQR309 reduces proliferation in endometrial cancer cells and endometrial cancer stem cells by decreasing CDK6 and increasing p27 and subsequently inducing G1-phase arrest. Inhibition of c-Myc/mtp53 cascade played a critical role in anti-endometrial cancer by PQR309. PQR309 may be a potential drug in anti-endometrial cancer[4]

PQR309 has anti-lymphoma activity as single agent and in combination in vitro and in vivo[5]. PQR309 shows only modest response but significant toxicity in 50 patients with heavily pretreated relapsed or refractory lymphoma of various histological subtype at continuous doses of 80mg and 60mg[6]. The MTD and RP2D of PQR309 is 80 mg of orally OD[2]

References:
[1]. Beaufils F, Cmiljanovic N, et al. 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology. J Med Chem. 2017;60(17):7524-7538.
[2]. Wicki A, Brown N, et al. First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with advanced solid tumors (SAKK 67/13). Eur J Cancer. 2018;96:6-16.
[3]. Yang K, Tang XJ, et al. PI3K/mTORC1/2 inhibitor PQR309 inhibits proliferation and induces apoptosis in human glioblastoma cells. Oncol Rep. 2020;43(3):773-782.
[4]. Hsin IL, Shen HP, et al. Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 Positive Feedback Loop Induces Cell Cycle Arrest by Dual PI3K/mTOR Inhibitor PQR309 in Endometrial Cancer Cell Lines. Cells. 2021;10(11):2916. Published 2021 Oct 27.
[5]. Tarantelli C, Gaudio E, et al. PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy. Clin Cancer Res. 2018;24(1):120-129.
[6]. Collins GP, Eyre TA, et al. A Phase II Study to Assess the Safety and Efficacy of the Dual mTORC1/2 and PI3K Inhibitor Bimiralisib (PQR309) in Relapsed, Refractory Lymphoma. Hemasphere. 2021;5(11):e656. Published 2021 Oct 27.

Chemical Properties

Cas No. 1225037-39-7 SDF
Synonyms PI3K-IN-2
Canonical SMILES NC1=NC=C(C2=NC(N3CCOCC3)=NC(N4CCOCC4)=N2)C(C(F)(F)F)=C1
Formula C17H20F3N7O2 M.Wt 411.38
Solubility DMSO : ≥ 50 mg/mL (121.54 mM) Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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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
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Average Rating: 5 ★★★★★ (Based on Reviews and 2 reference(s) in Google Scholar.)

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