GDC-0349,mTORInhibitor

GDC-0349 is a potent and selective ATP-competitive inhibitor of mTOR with IC₅₀ ~3.8 nM. It has remarkable selectivity over 266 kinases, including all isoforms of PI3K (less than 25% inhibition when tested at 1 μM against Invitrogen kinase panel). GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.  When dosed orally once daily in athymic mice in a MCF7-neo/Her2 tumor xenograft model (PI3K mutation), GDC-0349 inhibited tumor growth in a dose-dependent manner. It was also efficacious in other xenograft models, including PC3 (PTEN null) and 786-0 (VHL mutant). GDC-0349 inhibited 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. Currently GDC-0349 is in Phase I clinical trials to evaluate the safety and tolerability in patients with locally advanced or metastatic solid tumors or Non-Hodgkin's lymphoma. 

How to Use:

• In vitro: GDC-0349 was used at 1 µM in vitro and in cellular assays. 
• In vivo: GDC-0349 was orally dosed to mice at 30-80 mg/kg once per day.

Reference:

•  1. Zhonghua Pei, et al. Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349 (2013) ACS Med. Chem. Lett., 4 (1), pp 103–107