AT7867 Is a Potent and Oral Inhibitor of AKT and p70 S6 Kinase That Induces Pharmacodynamic Changes and Inhibits Human Tumor Xenograft Growth

Abstract

The serine/threonine kinase AKT plays a pivotal role in signal transduction events involved in malignant transformation and chemoresistance and is an attractive target for the development of cancer therapeutics. Fragment-based lead discovery, combined with structure-based drug design, has recently identified AT7867 as a novel and potent inhibitor of both AKT and the downstream kinase p70 S6 kinase (p70S6K) and also of protein kinase A. This ATP-competitive small molecule potently inhibits both AKT and p70S6K activity at the cellular level, as measured by inhibition of GSK3β and S6 ribosomal protein phosphorylation, and also causes growth inhibition in a range of human cancer cell lines as a single agent. Induction of apoptosis was detected by multiple methods in tumor cells following AT7867 treatment. Administration of AT7867 (90 mg/kg p.o. or 20 mg/kg i.p.) to athymic mice implanted with the PTEN-deficient U87MG human glioblastoma xenograft model caused inhibition of phosphorylation of downstream substrates of both AKT and p70S6K and induction of apoptosis, confirming the observations made in vitro. These doses of AT7867 also resulted in inhibition of human tumor growth in PTEN-deficient xenograft models. These data suggest that the novel strategy of AKT and p70S6K blockade may have therapeutic value and supports further evaluation of AT7867 as a singleagent anticancer strategy.

Improving chemoradiation efficacy by PI3-K/AKT inhibition

“…Various research groups have shown that inhibitors of the PI3-K/AKT pathway delay tumor growth in several xenografted cancer types, including cancers of the head and neck, breast, brain, colon and lung [73][74][75][76][77]. Interestingly, Schnell et al [78] found that the early effects of a dual PI3-K/mTOR inhibitor on the vasculature, resulting in reduced vascular leakage, were predictive for effects on tumor growth.…”

AT7867 Inhibits Human Colorectal Cancer Cells via AKT-Dependent and AKT-Independent Mechanisms

“…has recently developed a dual inhibitor of AKT and p70S6K1 (“S6K1”), named AT7867 [15]. This dual inhibitor was shown to block AKT-S6K1 activation and inhibit human tumor cell proliferation [15].…”

“…has recently developed a dual inhibitor of AKT and p70S6K1 (“S6K1”), named AT7867 [15]. This dual inhibitor was shown to block AKT-S6K1 activation and inhibit human tumor cell proliferation [15]. Although the effect of AT7867 on human CRC viability was examined by Grimshaw et al [15], this effect remains to be fully characterized.…”

p70S6 kinase is a critical node that integrates HER-family and PI3 kinase signaling networks

“…AT7867 has been shown to be an effective inhibitor of cancer cell growth both in vitro and in vivo [25]. Treatment of all three cell lines with AT7867 for 72 hours caused a dose-dependent decrease in growth with an average IC50 of approximately 4 μM (Figure 4A).…”

“…AT7867 has been demonstrated to inhibit the kinase activity of proteins other than p70S6K at the concentrations that caused cytotoxicity and apoptosis, such as other AGC kinases including Protein Kinase A (PKA) and AKT [25]. Therefore, we tested another structurally distinct compound, Ro31-8220, that has been shown to inhibit p70S6K activity.…”