PQR309
(Synonyms: PQR309) 目录号 : GC19300
PQR309 是一种有效的脑渗透性口服生物利用度泛 I 类 PI3K/mTOR 抑制剂，对 PI3Kα、PI3Kδ、PI3Kβ、PI3Kγ 和 mTOR 的 IC50 分别为 33nM、451nM、661nM、708nM 和 89nM .PQR309 在人脑胶质瘤细胞中通过抑制增殖、诱导细胞凋亡、诱导 G1 细胞周期停滞、抑制侵袭和迁移等方式发挥抗肿瘤作用。
Cas No.:1225037-39-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Human GBM cell lines (U87 and U251) |
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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℃. |
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Reaction Conditions |
0, 1, 5, 10, 20, 50 and 100µM |
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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]: | |
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Animal models |
Healthy male nude NIH rats |
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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. |
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Dosage form |
5, 10, 15mg/kg, oral administration |
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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. |
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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. |
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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.
PQR309 是一种有效的脑渗透性口服生物利用度泛 I 类 PI3K/mTOR 抑制剂，对 PI3Kα、PI3Kδ、PI3Kβ、PI3Kγ 和 mTOR 的 IC50 分别为 33nM、451nM、661nM、708nM 和 89nM [1][2].
PQR309 在人脑胶质瘤细胞中通过抑制增殖、诱导细胞凋亡、诱导 G1 细胞周期停滞、抑制侵袭和迁移等方式发挥抗肿瘤作用[3]。 PQR309 通过减少 CDK6 和增加 p27 并随后诱导 G1 期停滞来减少子宫内膜癌细胞和子宫内膜癌干细胞的增殖。 PQR309 对 c-Myc/mtp53 级联的抑制在抗子宫内膜癌中起着关键作用。 PQR309可能是一种潜在的抗子宫内膜癌药物[4]
PQR309 在体外和体内作为单一药物和联合药物均具有抗淋巴瘤活性[5]。 PQR309 在 50 例经过大量预处理的各种组织学亚型的复发性或难治性淋巴瘤患者中以 80 毫克和 60 毫克的连续剂量[6]显示出仅适度的反应，但显示出显着的毒性。 PQR309 的 MTD 和 RP2D 为 80 mg 口服 OD[2]
| Cas No. | 1225037-39-7 | SDF | |
| 别名 | PQR309 | ||
| Canonical SMILES | NC1=NC=C(C2=NC(N3CCOCC3)=NC(N4CCOCC4)=N2)C(C(F)(F)F)=C1 | ||
| 分子式 | C17H20F3N7O2 | 分子量 | 411.38 |
| 溶解度 | DMSO : ≥ 50 mg/mL (121.54 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
PI3K/mTORC1/2 inhibitor PQR309 inhibits proliferation and induces apoptosis in human glioblastoma cells
Oncol Rep2020 Mar;43(3):773-782.PMID: 32020210DOI: 10.3892/or.2020.7472
Glioblastoma (GBM) is the most common type of primary central nervous system tumor in adults, which has high mortality and morbidity rates, and short survival time, namely <15 months after the diagnosis and application of standard therapy, which includes surgery, radiation therapy and chemotherapy; thus, novel therapeutic strategies are imperative. The activation of the PI3K/AKT signaling pathway plays an important role in GBM. In the present study, U87 and U251 GBM cells were treated with the PI3K/mTORC1/2 inhibitor PQR309, and its effect on glioma cells was investigated. Cell Counting Kit‑8 assay, 5‑ethynyl‑2'‑deoxyuridine and colony formation assays revealed dose‑ and time‑dependent cytotoxicity in glioma cells that were treated with PQR309. Flow cytometry and western blotting revealed that PQR309 can significantly induce tumor cell apoptosis and arrest the cell cycle in the G1 phase. Furthermore, the expression levels of AKT, phosphorylated (p)‑AKT, Bcl‑2, Bcl‑xL, Bad, Bax, cyclin D1, cleaved caspase‑3, MMP‑9 and MMP‑2 were altered. In addition, the migration and invasion of glioma cells, as detected by wound healing, migration and Transwell invasion assays, exhibited a marked suppression after treating the cells with PQR309. These results indicated that PQR309 exerts an antitumor effect by inhibiting proliferation, inducing apoptosis, inducing G1 cell cycle arrest, and inhibiting invasion and migration in human glioma cells. The present study provides evidence supportive of further development of PQR309 for adjuvant therapy of GBM.
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
Cells2021 Oct 27;10(11):2916.PMID: 34831139DOI: 10.3390/cells10112916
Gene mutations in PIK3CA, PIK3R1, KRAS, PTEN, and PPP2R1A commonly detected in type I endometrial cancer lead to PI3K/Akt/mTOR pathway activation. Bimiralisib (PQR309), an orally bioavailable selective dual inhibitor of PI3K and mTOR, has been studied in preclinical models and clinical trials. The aim of this study is to evaluate the anticancer effect of PQR309 on endometrial cancer cells. PQR309 decreased cell viability in two-dimensional and three-dimensional cell culture models. PQR309 induced G1 cell cycle arrest and little cell death in endometrial cancer cell lines. It decreased CDK6 expression and increased p27 expression. Using the Proteome Profiler Human XL Oncology Array and Western blot assay, the dual inhibitor could inhibit the expressions of c-Myc and mtp53. KJ-Pyr-9, a c-Myc inhibitor, was used to prove the role of c-Myc in endometrial cancer survival and regulating the expression of mtp53. Knockdown of mtp53 lowered cell proliferation, Akt/mTOR pathway activity, and the expressions of c-Myc. mtp53 silence enhanced PQR309-inhibited cell viability, spheroid formation, and the expressions of p-Akt, c-Myc, and CDK6. This is the first study to reveal the novel finding of the PI3K/mTOR dual inhibitor in lowering cell viability by abolishing the PI3K/Akt/mTOR/c-Myc/mtp53 positive feedback loop in endometrial cancer cell lines.
PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy
Clin Cancer Res2018 Jan 1;24(1):120-129.PMID: 29066507DOI: 10.1158/1078-0432.CCR-17-1041
Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models.Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.Results: PQR309 had in vitro antilymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab. Sensitivity to PQR309 was associated with specific baseline gene-expression features, such as high expression of transcripts coding for the BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene-expression signatures induced by PQR309 and by other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib.Conclusions: On the basis of these results, PQR309 appeared as a novel and promising compound that is worth developing in the lymphoma setting. Clin Cancer Res; 24(1); 120-9. ©2017 AACR.
A Phase II Study to Assess the Safety and Efficacy of the Dual mTORC1/2 and PI3K Inhibitor Bimiralisib (PQR309) in Relapsed, Refractory Lymphoma
Hemasphere2021 Oct 27;5(11):e656.PMID: 34901759DOI: 10.1097/HS9.0000000000000656
Bimiralisib is an orally bioavailable pan-phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitor which has shown activity against lymphoma in preclinical models. This phase I/II study evaluated the response rate to bimiralisib at 2 continuous dose levels (60 mg and 80 mg) in patients with relapsed/refractory lymphoma. Fifty patients were enrolled and started treatment. The most common histologies were diffuse large B-cell lymphoma (n = 17), follicular lymphoma (n = 9), T-cell lymphoma (n = 8), and others (mostly indolent). Patients had been treated with a median of 5 prior lines of treatment and 44% were considered refractory to their last treatment. Mean duration of treatment (and standard deviations) with 60 mg once daily (o.d.) was 1.3 ± 1.2 months, and with 80 mg o.d. 3.7 ± 3.9 months. On an intention to treat analysis, the overall response rate was 14% with 10% achieving a partial response and 4% a complete response. Thirty-six percent of patients were reported as having stable disease. No dose-limiting toxicities were observed during the phase I portion of the study. Overall, 70% of patients had a grade 3 treatment emergent adverse events (TEAE) and 34% had a grade 4 TEAE; 28% of patients discontinued treatment due to toxicity. The most frequent TEAEs grade ≥3 was hyperglycemia (24%), neutropenia (20%), thrombocytopenia (22%), and diarrhea (12%). Per protocol, hyperglycemia required treatment with oral antihyperglycemic agents in 28% and with insulin in 14%. At 60 mg or 80 mg continuous dosing, bimiralisib showed modest efficacy with significant toxicity in heavily pretreated patients with various histological subtypes of lymphoma.
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 Cancer2018 Jun;96:6-16.PMID: 29660598DOI: 10.1016/j.ejca.2018.03.012
Background: PQR309 is an orally bioavailable, balanced pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor.
Patients and methods: This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D).
Results: Twenty-eight patients were included in six dosing cohorts and treated at a daily PQR309 dose ranging from 10 to 150 mg. Common adverse events (AEs; ≥30% patients) included fatigue, hyperglycaemia, nausea, diarrhoea, constipation, rash, anorexia and vomiting. Grade (G) 3 or 4 drug-related AEs were seen in 13 (46%) and three (11%) patients, respectively. Dose-limiting toxicity (DLT) was observed in two patients at 100 mg OD (>14-d interruption in PQR309 due to G3 rash, G2 hyperbilirubinaemia, G4 suicide attempt; dose reduction due to G3 fatigue, G2 diarrhoea, G4 transaminitis) and one patient at 80 mg (G3 hyperglycaemia >7 d). PK shows fast absorption (Tmax 1-2 h) and dose proportionality for Cmax and area under the curve. A partial response in a patient with metastatic thymus cancer, 24% disease volume reduction in a patient with sinonasal cancer and stable disease for more than 16 weeks in a patient with clear cell Bartholin's gland cancer were observed.
Conclusion: The MTD and RP2D of PQR309 is 80 mg of orally OD. PK is dose-proportional. PD shows PI3K pathway phosphoprotein downregulation in paired tumour biopsies. Clinical activity was observed in patients with and without PI3K pathway dysregulation.