Abstract DDT02-01: GDC-0068: A novel, selective, ATP-competitive inhibitor of Akt
Authors: Lin Kui 
Published: June 2012

Abstract
Akt is one of the most frequently activated protein serine/threonine kinases in human malignancies. As a central node of the PI3K-Akt-mTOR pathway, Akt plays a critical role in cancer initiation, progression and therapeutic resistance, representing an important and attractive cancer therapeutic target.
Initial optimization of inhibitors, identified from a high-throughput screen against Akt1, led to potent pan-Akt inhibitors with poor selectivity over other kinases (e.g., the closely related protein kinase A, PKA). Guided by crystal structures of Akt1, Akt2, and PKA in complex with compounds, selectivity over PKA was improved dramatically. Subsequent optimization of pharmaceutical properties led to the discovery of GDC-0068, a potent, orally bioavailable, ATP-competitive pan-Akt inhibitor (enzymatic IC50 values of 5 to 30 nM for all 3 isoforms), that is highly selective over other kinases, including &gt;100-fold selectivity over PKA.
GDC-0068 blocks Akt signaling as demonstrated by dose-dependent inhibition of the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. In the PTEN-deficient prostate cancer cell line LNCaP, GDC-0068 has a cellular IC50 value of 176 nM for the phosphorylation of the Akt substrate, PRAS40. In addition, GDC-0068 inhibits cell cycle progression and viability of cancer cell lines driven by Akt signaling, including those with defects in the tumor suppressor PTEN, oncogenic mutations in PIK3CA, and amplification of HER2. When dosed orally in xenograft cancer models, GDC-0068 induced pharmacodynamic knockdown of key Akt signaling outputs that correlated with drug exposure. Antitumor efficacy was observed in multiple xenograft tumor models, including those of human prostate, breast, ovarian, colon, glioma and melanoma origins. Tumor stasis or regression was achieved at well-tolerated oral doses in xenograft models predicted to be dependent on activated Akt signaling, such as the PTEN-deficient prostate cancer models LNCaP and PC3, and the PIK3CA H1047R mutant breast cancer model KPL-4. Consistent with the role of Akt in a survival pathway, GDC-0068 also demonstrated enhanced antitumor efficacy when combined with other therapeutic agents.
Unlike allosteric inhibitor, whose potency was negatively affected by the activating mutations in Akt1, such as the E17K mutation found in human cancers, GDC-0068-like ATP-competitive inhibitors target activated Akt and exhibit enhanced potency on mutant Akt1. Novel discoveries on the mechanistic effects of ATP-competitive Akt inhibitors on the Akt protein will be discussed.
In summary, GDC-0068 is a novel, highly selective ATP-competitive Akt inhibitor with compelling selectivity, efficacy, and oral pharmacokinetics that support its clinical development as an anti-cancer agent. The selective activity in cancer cells with activated Akt signaling allows for a rational strategy to potentially identify patients who will benefit in clinical trials. GDC-0068 is currently in phase I clinical trials in cancer patients.
Special thanks to the Akt project teams at Array BioPharma and Genentech. Inc.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr DDT02-01. doi:10.1158/1538-7445.AM2011-DDT02-01