1927857-56-4|PQR620|CsnPharm

CAS No.: 1927857-56-4

PQR620 Catalog No. CSN19143

Synonyms: PQR620

PRQ620 is a highly potent and selective mTORC1/2 inhibitor, shows anti-tumor effects in vitro and in vivo.

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400-920-2911

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技术信息

生物活性

描述Mammalian target of rapamycin (mTOR) signaling pathway plays a fundamental role in cell proliferation, differentiation, growth and survival. PQR620 is a novel potent and selective brain penetrant inhibitor of mTORC1/2 with a >1000-fold selectivity towards mTOR over PI3Kα in enzymatic binding assays. In A2058 melanoma cells, PQR620 demonstrates inhibition of protein kinase B (pSer473) and ribosomal protein S6 (pSer235/236) phosphorylation with IC50 values of 0.2 μM and 0.1 μM, respectively. It also demonstrates its potency to prevent cancer cell growth in an NTRC 44 cancer cell line panel, resulting in a ¹⁰log(IC50) of 2.86(nM). PQR620 has a median IC50 of 250 nM when tested on 44 lymphoma cell lines. Activity is higher in B cell than in T cell tumors (median IC50s: 250 nM vs 450 nM; P=0.002). At 72h, anti-tumor activity of PQR620 is mostly cytostatic and apoptosis induction is seen only in 6/44 cell lines (13%). Sensitivity to PQR620 or apoptosis induction does not differ between DLBCL and MCL, and they are not affected by the DLBCL cell of origin, by TP53 status or by the presence of MYC or BCL2 translocations. The activity of PQR620 as single agent undergoes in vivo evaluation in two DLBCL models, the germinal center B cell type DLBCL (GCB-DLBCL) SU-DHL-6 and the activated B cell-like DLBCL (ABC-DLBCL) RIVA. Treatments with PQR620 (100 mg/kg dose per day, Qd×7/w) start with 100-150 mm³ tumors and are carried for 14 (SU-DHL-6) or 21 days (RIVA). In both models, PQR620 determines a 2-fold decrease of the tumor volumes in comparison with control, with significant differences in both SU-DHL-6 (D7, D9, D11, D14; P<0.005) and RIVA (D14, D16, D19, D21; P<0.005).

动物研究

剂量

Rat: 10 mg/kg^[2] (p.o., MTD = 30 mg/kg) Mice: 50 mg/kg^[2] (p.o., MTD = 150 mg/kg), 100 mg/kg^[3] (p.o.)

给药途径

p.o.

动物药代数据

Animal	Mice^[2]	Rats^[2]
Dose	50 mg/kg	10 mg/kg
Administration	p.o.	p.o.
AUC_0-8		406 μg·h/ml
Brain: blood		~1:1
T_max	0.5 h	0.5 h
AUC_0→∞	31691 ng·h/ml
CL/F	1578 ml/(h·kg)
C_z	1455 ng/ml
V_z/F	12091 ml/kg
T_z	8.0 h
C_max	4835 ng/ml	1355 ng/g
T_1/2z	5.3 h

参考文献

[2] Rageot D, Bohnacker T, et al. Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders. J Med Chem. 2018 Nov 21;61(22):10084-10105.
[3] Tarantelli C, Gaudio E, et al. The Novel TORC1/2 Kinase Inhibitor PQR620 Has Anti-Tumor Activity in Lymphomas as a Single Agent and in Combination with Venetoclax. Cancers (Basel). 2019 Jun 4;11(6). pii: E775.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.2448 mL
- 11.2241 mL
- 22.4482 mL
- 5 mM
- 0.4490 mL
- 2.2448 mL
- 4.4896 mL
- 10 mM
- 0.2245 mL
- 1.1224 mL
- 2.2448 mL

技术信息

CAS号

1927857-56-4

储存条件

粉末: Keep in dark place,Inert atmosphere,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C21H25F2N7O2

运输

蓝冰

分子量

445.47

别名

PQR620

溶解度

DMSO	20.0 mg/mL (44.9 mM)
Water	Insoluble
Ethanol	2.0 mg/mL (4.5 mM)

动物实验配方

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