GDC-0349 is a remarkably selective mTOR inhibitor, with less than 25% inhibition of 266 kinases, including all isoforms of PI3K when tested at 1 μM[1].
体内研究
Upon oral administration once daily in athymic mice carrying MCF7-neo/Her2 tumor xenografts with PI3K mutation, GDC-0349 effectively suppresses tumor growth in a dose-dependent manner, achieving stasis (99% Tumor Growth Inhibition, TGI) at the maximum tolerated dose. Throughout the treatment, changes in body weight remain below 10% even at the highest administered dose. GDC-0349 also demonstrates efficacy in additional xenograft models, such as PC3 (PTEN null) and 786-0 (VHL mutant). Comparable levels of tumor growth inhibition are observed when GDC-0349 is administered once every three days at higher doses compared to once-daily dosing. Additionally, GDC-0349 exhibits approximately 10-fold reduced free plasma clearance in both mice (100 mL/min/kg) and rats (171 mL/min/kg) [1].
体外研究
GDC-0349 is a remarkably selective mTOR inhibitor, with less than 25% inhibition of 266 kinases, including all isoforms of PI3K when tested at 1 μM[1].
GDC-0349 细胞实验
Cell Line
Concentration
Treated Time
Description
References
A549 cells
5-500 nM
24-96 hours
GDC-0349 inhibited A549 cell viability in a concentration- and time-dependent manner, significantly reducing colony formation and proliferation, inducing G1-S phase arrest, and inhibiting cell migration and invasion.
Cell Death Dis. 2020 Nov 5;11(11):951.
BEAS-2B epithelial cells and primary human lung epithelial cells
100 nM
GDC-0349 did not induce viability reduction or apoptosis in BEAS-2B epithelial cells and primary human lung epithelial cells.
Cell Death Dis. 2020 Nov 5;11(11):951.
Primary human NSCLC cells (NSCLC-1/-2/-3)
100 nM
GDC-0349 significantly reduced viability, proliferation, and migration of primary NSCLC cells.
Cell Death Dis. 2020 Nov 5;11(11):951.
GDC-0349 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
SCID mice
A549 or NSCLC-1 xenograft model
Oral
10 or 30 mg/kg
Once daily for 21 days
Oral administration of GDC-0349 significantly inhibited the growth of A549 and NSCLC-1 xenografts without causing significant toxicity.
Cell Death Dis. 2020 Nov 5;11(11):951.
Athymic mice
MCF7-neo/Her2 tumor xenograft model
Oral
10, 20, 30, 40, 50, 60, 70, 80 mg/kg
Once daily
To evaluate the dose-dependent antitumor efficacy of GDC-0349 in the MCF7-neo/Her2 tumor model, results showed tumor growth stasis (99% TGI) at the maximum tolerated dose.
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