Yap, T. A., Walton, M. I., Grimshaw, K. M., te Poele, R. H., Eve, P. D., Valenti, M. R., Brandon, A. K. D., Martins, V., Zetterlund, A., Heaton, S. P., Heinzmann, K., Jones, P. S., Feltell, R. E., Reule, M., Woodhead, S. J., Davies, T. G., Lyons, J. F., Raynaud, F. I., Eccles, S. A., Workman, P., Thompson, N. T., Garrett, M. D. (2012) AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity. CLINICAL CANCER RESEARCH, 18 (14). pp. 3912-3923. ISSN 1078-0432

Full text not available from this repository.

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 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. Clin Cancer Res; 18(14); 3912-23. (C)2012 AACR.

Item Type:	Article
Authors (ICR Faculty only):	Raynaud, Florence and Eccles, Sue and Workman, Paul and Garrett, Michelle
All Authors:	Yap, T. A., Walton, M. I., Grimshaw, K. M., te Poele, R. H., Eve, P. D., Valenti, M. R., Brandon, A. K. D., Martins, V., Zetterlund, A., Heaton, S. P., Heinzmann, K., Jones, P. S., Feltell, R. E., Reule, M., Woodhead, S. J., Davies, T. G., Lyons, J. F., Raynaud, F. I., Eccles, S. A., Workman, P., Thompson, N. T., Garrett, M. D.
Additional Information:	ISI Document Delivery No.: 988PN Times Cited: 0 Cited Reference Count: 35 Yap, Timothy A. Walton, Mike I. Grimshaw, Kyla M. te Poele, Robert H. Eve, Paul D. Valenti, Melanie R. Brandon, Alexis K. de Haven Martins, Vanessa Zetterlund, Anna Heaton, Simon P. Heinzmann, Kathrin Jones, Paul S. Feltell, Ruth E. Reule, Matthias Woodhead, Steven J. Davies, Thomas G. Lyons, John F. Raynaud, Florence I. Eccles, Suzanne A. Workman, Paul Thompson, Neil T. Garrett, Michelle D. Astellas; Piramed Pharma; Astex Pharmaceuticals; Cancer Research UK (CR-UK)[C309/A8274]; CR-UK[C51/A6883, C51/A7401, C309/A8992]; Marie Curie Early Stage Funding; Astex Therapeutics; NHS T. A. Yap, M. I. Walton, R. H. te Poele, P. D. Eve, M. R. Valenti, A. K. de Haven Brandon, V. Martins, A. Zetterlund, S. P. Heaton, K. Heinzmann, F. I. Raynaud, S. A. Eccles, P. Workman, and M. D. Garrett are current or former employees of The Institute of Cancer Research, which has a commercial interest in the development of AKT inhibitors, including AT13148, and operates a rewards for inventors scheme. K. M. Grimshaw, R. Feltell, M. Reule, S.J. Woodhead, T. G. Davies, J.F. Lyons, and N.T. Thompson are current or former employees of Astex Therapeutics, which also has a commercial interest in the development of AKT inhibitors including AT13148. Both Astex Therapeutics and The Institute of Cancer Research have been involved in a commercial collaboration with Cancer Research Technology Limited (CRT) to discover and develop inhibitors of AKT and intellectual property arising from this program has been licensed to AstraZeneca. P. Workman has a commercial research grant from Yamanouchi (now Astellas), Piramed Pharma, and Astex Pharmaceuticals; ownership interest (including patents) from Piramed Pharma (acquired by Roche) and Chroma Therapeutics; and is a consultant/advisory board member for Piramed Pharma, Chroma Therapeutics, Novartis, Wilex, and Nextech Ventures.Grant support was provided to T. A. Yap, M. I. Walton, P. D. Eve, M. R. Valenti, A. K. de Haven Brandon, V. Martins, A. Zetterlund, F. I. Raynaud, S. A. Eccles, P. Workman, and M. D. Garrett by Cancer Research UK (CR-UK) grant C309/A8274; to S. P. Heaton by CR-UK grant C51/A6883; to R. H. te Poele by CR-UK grant C51/A7401; to K. Heinzmann by Marie Curie Early Stage Funding; and to P. Workman by CR-UK grant number C309/A8992. P. Workman is a Cancer Research Life Fellow. Additional support was provided to S. A. Eccles and M. D. Garrett by The Institute of Cancer Research. This work was carried out as part of a funded research collaboration with Astex Therapeutics. The authors acknowledge NHS funding to the NIHR Biomedical Research Centre. Amer assoc cancer research Philadelphia
Uncontrolled Keywords:	transcription factors phosphoinositide 3-kinase human cancer protein pi3k expression pathway akt pharmacology downstream
Research teams:	ICR divisions > Cancer Therapeutics > Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) ICR divisions > Cancer Therapeutics > Tumour Biology & Metastasis ICR divisions > Cancer Therapeutics > Cell Cycle Control (including GCLP Biomarker Group) ICR divisions > Cancer Therapeutics > Signal Transduction & Molecular Pharmacology
Depositing User:	Alexander Smithson
Date Deposited:	04 Oct 2012 09:58
Last Modified:	08 Dec 2014 05:12
URI:	http://publications.icr.ac.uk/id/eprint/11923

Actions (login required)

View Item