Background:

GDC-0349 is a potent, selective, ATP-competitive inhibitor of (Mammalian target of rapamycin) mTOR with Ki value of 3.8nM [1].

GDC-0349 is a remarkably selective mTOR inhibitor, with less than 25% inhibition of 266 kinases, including all isoforms of PI3K. GDC-0349 inhibited mTOR downstream markers , involving phospho-Akt(s473) and phospho-4EBP1 in an in vivo PK/PD study in mouse, consistent with an inhibition of mTORC1/mTORC2 complexes [1].

GDC-0349 inhibited tumor growth in a dose-dependent manner when dosed orally once daily in athymic mice in a MCF7-neo/Her2 tumor xenograft model (PI3K mutation). GDC-0349 was also efficacious in other xenograft models, including PC3 (PTEN null) and 786-0 (VHL mutant). However, GDC-0349 showed only modest tumor growth delay in the A549 mouse xenograft model (KRas mutant, LKB1 deficient) [1].

参考文献:
[1] Pei,?Z.; Blackwood,?E.; Liu,?L.; Malek,?S.; Belvin,?M.; Koehler,?M. F. T.; Ortwine,?D. F.; Chen,?H.; Cohen,?F.; Kenny,?J. R.; Bergeron,?P.; Lau,K.; Ly,?C.; Zhao,?X.; Estrada,?A. A.; Truong,?T.; Epler,?J. A.; Nonomiya,?J.; Trinh,?L.; Sideris,?S.; Lesnick,?J.; Bao,?L.; Vijapurkar,?U.; Mukadam,S.; Tay,?S.; Deshmukh,?G.; Chen,?Y.-H.; Ding,?X.; Friedman,?L.; Lyssikatos,?J. P.Discovery and biological profiling of potent and selective mTOR inhibitor GDC-0349?ACS Med. Chem. Lett.?2013,?4,?103–?107