GDC-0349 is a potent small molecule mTOR inhibitor with Ki of 3.8 nM. GDC-0349 inhibits downstream markers of mTOR, including phospho-4EBP1 and phospho-Akt(S473) in an in vivo PK/PD study in mouse, consistent with an inhibition of both mTORC1 and mTORC2 complexes. GDC-0349 inhibits tumor growth in a dose-dependent manner when dosed orally once daily in athymic mice in a MCF7-neo/Her2 tumor xenograft model. GDC-0349 is also efficacious in other xenograft models, including PC3 (PTEN null) and 786-O (VHL mutant). GDC-0349 is currently in a Phase I clinical trials in the treatment with solid tumors or Non-Hodgkin's lymphoma.
|Preparation method||Compound activity is tested in 10 point dose curves starting at the highest final concentration of 10 uM. They are serially diluted in 100% DMSO prior to further dilution with assay buffer. The reaction mixture (8 uls) containing 0.25 nM mTOR+GBL enzyme, 400 nM GFP-4E-BP1, 8 uM ATP, 50 mM Hepes pH 7.5, 0.01% Tween 20, 10 mM MnCl2, 1 mM EGTA, 1 mM DTT, 1% DMSO (+/- compound) is incubated at room temperature for 30 minutes. 8 uL of solution containing 2 nM Tb-anti-p4E-BP1 antibody & 10 mM EDTA diluted TR-FRET buffer is then added and incubated for 30 minutes to stop the reaction. The plate is scanned with the Envision plate reader. Ki values are calculated in Assay Explorer using the Morrison ATP-competitive tight binding equation for Ki apparent determination.|
|Animal models||MCF7-neo/Her-2 mouse xenograft breast cancer model|
|Formulation||0.5% methylcellulose/0.2% Tween 80 (MCT)|
|Dosages||10, 20, 30, 40, 50, 60, 70, and 80 mg/kg QD for 24 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 90 mg/mL|
Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349.
Pei Z, et al. ACS Med Chem Lett. 2012 Nov 29;4(1):103-7. PMID: 24900569.
Pyrimidoaminotropanes as potent, selective, and efficacious small molecule kinase inhibitors of the mammalian target of rapamycin (mTOR).
Estrada AA, et al. J Med Chem. 2013 Apr 11;56(7):3090-101. PMID: 23473235.
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