GDC-0349

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].

References:
[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

Autophagy induction contributes to GDC-0349 resistance in head and neck squamous cell carcinoma (HNSCC) cells.[Pubmed:27291151]

Biochem Biophys Res Commun. 2016 Aug 19;477(2):174-80.

Dysregulation of mammalian target of rapamycin (mTOR) signaling contributes to head and neck squamous cell carcinoma (HNSCC) tumorigenesis and progression. In the current study, we tested the anti-HNSCC cell activity by GDC-0349, a selective ATP-competitive inhibitor of mTOR. We showed that GDC-0349 inhibited proliferation of established and primary human HNSCC cells bearing high-level of p-AKT/p-S6K. Further, it induced caspase-dependent apoptosis in the HNSCC cells. GDC-0349 blocked mTORC1 and mTORC2 activation, yet it simultaneously induced autophagy activation in HNSCC cells. The latter was evidenced by induction of LC3B-II, Beclin-1 and Autophagy-related (ATG)-7, as well as downregulation of p62. Autophagy inhibitors (3-methyladenine and bafilomycin A1) or ATG-7 siRNA dramatically potentiated GDC-0349's cytotoxicity against HNSCC cells. Intriguingly, we showed that ceramide (C14), a pro-apoptotic sphingolipid, also induced ATG-7 degradation, and sensitized HNSCC cells to GDC-0349. Collectively, the preclinical study provided evidences to support GDC-0349 as a promising anti-HNSCC agent. GDC-0349 sensitization may be achieved via autophagy inhibition.

Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349.[Pubmed:24900569]

ACS Med Chem Lett. 2012 Nov 29;4(1):103-7.

Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead 1 culminated in the discovery of clinical development candidate 8h, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.

GDC-0349 is a potent and selective ATP-competitive mTOR inhibitor with a Ki of 3.8 nM. GDC-0349 inhibits of both mTORC1 and mTORC2 complexes.

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