Dataset Information

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

ABSTRACT: 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 demonstrated. 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 due to 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 demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial.

ORGANISM(S): Homo sapiens

PROVIDER: GSE38008 | GEO | 2012/07/20

SECONDARY ACCESSION(S): PRJNA167208

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description: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 demonstrated. 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 due to 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 demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial. The PTEN-deficient U87MG glioblastoma cell line was treated for 6 hours with vehicle control (DMSO) or to different concentrations of AT13148 and CCT128930 (0.1uM, 1xGI50 and 3XGI50).

Project description:We show that roscovitine; a cyclin-dependent kinases inhibitor; given to mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation and fibrosis. It also restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that Roscovitine induced a limited set of proteins associated with lipid metabolism, fatty acid oxidation metabolism and adipose tissue remodeling but suppressed expression of a larger array of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. Furthermore, the phosphoproteome analysis identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases [e.g., CDKs and MAPKs], AGC kinases [e.g., S6K and PKC isoforms], and CAMK kinases [e.g., SIK1 and SIK2]). Pathway enrichment analysis of annotated kinase-substrate pairs showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and phosphatidylcholine and creatine biosynthesis are enriched following roscovitine treatment. The increased creatine pathways combined with more active mitochondria in eWAT may contribute to roscovitine-induced weight loss. Surprisingly, we found that unlike for eWAT, roscovitine led to up regulation of large sets of proteins and phosphosites in brown adipose tissue (BAT). Analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups (AGC kinases [e.g., PKD1 and PKA] and CMGC kinases [e.g., CDKs and MAPKs]. Among the top enriched pathways of kinase-substrate pairs were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling, suggesting that roscovitine led to a metabolically more active BAT. Overall, roscovitine treatment led to restoration of mitochondrial activity in BAT and eWAT suppressed by HFD, likely accounting for enhanced energy expenditure and weight loss.

Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure