Description
GDC-0349 is a potent and selective ATP-competitive inhibitor of mTOR with Ki of 3.8 nM, 790-fold inhibitory effect against PI3Kα and other 266 kinases. Phase 1.
Storage
2 years -20 centigrade Powder; 2 weeks 4 centigrade in DMSO; 6 months -80 centigrade in DMSO.
Molecular Formula
C24H32N6O3
Chemical Name
Urea, N-ethyl-N'-[4-[5,6,7,8-tetrahydro-4-[(3S)-3-methyl-4-morpholinyl]-7-(3-oxetanyl)pyrido[3,4-d]pyrimidin-2-yl]phenyl]-
Solubility
DMSO 91 mg/mL; Water <1 mg/mL; Ethanol 6 mg/mL
In vitro
GDC-0349 has remarkable selectivity over 266 kinases, including all isoforms of PI3K. 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.
In vivo
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 inhibits tumor growth in a dose-dependent manner. It is also efficacious in other xenograft models, including PC3 (PTEN null) and 786-O (VHL mutant).
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