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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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]
| 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. |
|
| 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。
Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet