GDC-0326

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种有效的、选择性的、口服的 PI3Kα 抑制剂，Ki 为 0.2 nM；其选择性分别是 PI3Kβ、PI3Kδ 和 PI3Kγ 的 133 倍、20 倍和 33 倍。

A potent, selective, orally available PI3Kα inhibitor with Ki of 0.2 nM; displays 133, 20 and 33-fold selectivity over PI3Kβ, PI3Kδ and PI3Kγ, respectively; inhibits MCF7-neo/HER2 and PC3 cells proliferation with IC50 of 0.1 uM and 2.2 uM, respectively; reduces tumor growth as well as vascular area in vivo, also reduces the incidence of liver and lymph node metastasis.

GDC-0326 is highly selective over other kinases. In a panel of 235 kinases, only one is inhibited by >50% by GDC-0326 when tested at 1 μM. GDC-0326 is not an inhibitor of cytochrome P450 enzymes tested (IC50>10 μM against 3A4, 2C9 1A2, 2C19, 2D6), is highly permeable in MDCK cells and has thermodynamic solubility of 82 μg/mL at pH 7.4.

GDC-0326 is highly stable in human and rat liver microsomes, and there is a good correlation with in vivo rat clearance. It is found to have consistently low clearance and high oral bioavailability across species tested, enabling significant sustained free drug levels. Daily administration of GDC-0326orally at 0.78, 1.56, 3.25, 6.25, or 12.5 mg/kg results in dose-dependent increase in TGI (73%, 79%, 83%, 101%, and 110%, respectively) and tumor regressions (6 PRs out of 10 animal at 6.25 and 12.5 mg/kg) when compared to vehicle treated mice. Daily administration of GDC-0326 orally at 0.78, 1.56, 3.25, 6.25, or 12.5 mg/kg also results in dose-dependent increase in TGI (73%, 97%, 97%, 122%, and 121%, respectively) in the KPL-4 xenograft model. Notably, maximum efficacy of GDC-0326 is observed at 6.25 mg/kg in the KPL-4 model based on TGI and tumor regressions (9 PRs and 1 CR out of 10 animal treated) when compared to vehicle treated mice. Doses of GDC-0326 up to 12.5 mg/kg are well tolerated based on less than 10% body weight loss (data not shown).

GDC 0326 | GDC0326

PI3K/Akt/mTOR signaling

PI3K

PI3Kα

Cancer

——

1282514-88-8

382.424

C19H22N6O3

>98% (HPLC)

DMSO: 69 mg/mL (180.5 mM); Water: Insoluble （ < 1 mg/ml refers to the product slightly soluble or insoluble )

C[C@H](OC1=CC=C2C3=NC(C4=NC=NN4C(C)C)=CN3CCOC2=C1)C(N)=O

(S)-2-((2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide

(-20℃)

With Ice Pack

≥ 2 years