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Journal Article

PMID

(22781553)

Authors

Yap TA, Walton MI, Grimshaw KM, Te Poele RH, Eve PD, Valenti MR, de Haven Brandon AK, Martins V, Zetterlund A, Heaton SP, Heinzmann K, Jones PS, Feltell RE, Reule M, Woodhead SJ, Davies TG, Lyons JF, Raynaud FI, Eccles SA, Workman P, Thompson NT, Garrett MD

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	18	14	2012 Jul 15	3912-23	Clin Cancer Res

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Abstract Text

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.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.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
AT13148	AT13148	3	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AT13148		AT-13148\|AT 13148	AKT Inhibitor (Pan) - ATP competitive 7 PKA Inhibitor 2	AT13148 is a small molecule ATP-competitive inhibitor of AGC kinases including AKT1, AKT2, AKT3, p70S6K (RPS6KB1), PKA (PRKACA), ROCK1, ROCK2, RSK1, and SGK3, which results in decreased growth of tumor cells (PMID: 22781553, PMID: 25840982, PMID: 32616501).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN loss	uterine corpus sarcoma	sensitive	AT13148	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AT13148 inhibited tumor growth in a PTEN-deficient human uterine sarcoma cell line xenograft model (PMID: 22781553).	22781553
PIK3CA mutant	breast cancer	sensitive	AT13148	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a ERBB3 (HER3) positive breast cancer cell line xenograft model harboring a PIK3CA mutation was demonstrated decreased tumor growth when treated with AT13148 (PMID: 22781553).	22781553
PTEN loss	prostate cancer	sensitive	AT13148	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AT13148 inhibited tumor growth in a PTEN-deficient human prostate cancer cell line xenograft model (PMID: 22781553).	22781553

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