AT13148 is a novel, oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity

Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including Akt, p70S6 kinase, PKA, SGK and Rho kinase is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component.

Experimental design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148.

Results: AT13148 caused substantial blockade of Akt, p70S6K, PKA, ROCK, and SGK substrate phosphorylation and induced Apoptosis in a concentration and time-dependent manner in Cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate Cancer, and PTEN-deficient MES-SA uterine tumor xenografts was shown. We show for the first time that induction of Akt phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of Akt, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on Apoptosis genes, whereas the selective Akt Inhibitor CCT128930 modulates cell-cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 as a result of compensatory feedback loops was observed.

Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which shows a distinct mechanism of action from other Akt inhibitors. AT13148 will now be assessed in a first-in-human phase I trial.