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Chemical Structure| 1386874-06-1 同义名 : LY3023414;GTPL8918
CAS号 : 1386874-06-1
货号 : A173638
分子式 : C23H26N4O3
纯度 : 99%+
分子量 : 406.478
MDL号 : MFCD28411368
存储条件：

粉末 Inert atmosphere,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(123.01 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • PI3K

  • mTOR

  • DNA-PK
描述 The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival. LY3023414 is a complex fused imidazoquinolinone with high solubility across a wide pH range designed to inhibit class I PI3K isoforms and mTOR kinase. The IC50 values of LY3023414 towards PI3K family members are 6.07 nM, 77.6 nM, 38 nM, 23.8 nM, 4.24 nM and 165 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, DNA-PK and mTOR, respectively. The compound is a novel, potent ATP-competitive inhibitor that demonstrates activity against PI3K, mTOR, and DNA-PK, thereby inducing cell-cycle effects and inhibiting cancer cell viability. Downstream target inhibition by LY3023414 occurs rapidly via an intermittent “on/off” mechanism that may enhance the drug's clinical tolerability, which may in turn allow LY3023414 to overcome some of the toxicities associated with PI3K/mTOR inhibitors and potentially reduce the emergence of feedback mechanisms leading to resistance. In vitro, inhibition of PI3K/AKT/mTOR signaling by LY3023414 caused G1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel screens. In vivo, LY3023414 demonstrated high bioavailability and dose-dependent dephosphorylation of PI3K/AKT/mTOR pathway downstream substrates such as AKT, S6K, S6RP, and 4E-BP1 for 4 to 6 hours. In vivo mouse studies, LY3023414 was formulated in 1% HEC in distilled water containing 0.25% polysorbate 80 and 0.05% Dow-Corning Antifoam 1510-US and administered by oral gavage (final volume 0.2 mL) at 3, 6, or 10 mg/kg twice daily for 28 days which resulted in dose-responsive inhibition of tumor growth in the PTEN-deleted U87 MG xenograft model[4].
作用机制 The compound binds in a pocket bounded by side-chain residues of Met953 and Ile963 on one side and Trp812 and Ile831 on the other. It makes a hydrogen bond with the main-chain amide of Val882 and a CH···O interaction with the main-chain carbonyl of Glu880. It additionally interacts with the tyrosine hydroxyl of Tyr867 and the main-chain amide and side-chain of Asp964[4].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.46mL

0.49mL

0.25mL

12.30mL

2.46mL

1.23mL

24.60mL

4.92mL

2.46mL
参考文献

[1]Smith MC, Mader MM, et al. Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth. Mol Cancer Ther. 2016 Oct;15(10):2344-2356.

[2]Zaidi AH, Kosovec JE, et al. PI3K/mTOR Dual Inhibitor, LY3023414, Demonstrates Potent Antitumor Efficacy Against Esophageal Adenocarcinoma in a Rat Model. Ann Surg. 2017 Jul;266(1):91-98.

[3]Zheng L, Li H, et al. Autophagy inhibition sensitizes LY3023414-induced anti-glioma cell activity in vitro and in vivo. Oncotarget. 2017 Oct 27;8(58):98964-98973.

[4]Smith MC, Mader MM, Cook JA, Iversen P, Ajamie R, Perkins E, Bloem L, Yip YY, Barda DA, Waid PP, Zeckner DJ, Young DA, Sanchez-Felix M, Donoho GP, Wacheck V. Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth. Mol Cancer Ther. 2016 Oct;15(10):2344-2356.