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Cancer Chemistry

Abstract LB-116: GSK2334470: A potent and highly selective inhibitor of PDK1

Jeffrey M. Axten, Jesus R. Medina, Arthur Shu, William H. Li, Yanhong Feng, M. Phillip DeYoung, Christine M. Gardiner, Antony R. Chadderton, Melissa Dumble, Qi Liu and Sridhar Rabindran
Jeffrey M. Axten
1GlaxoSmithKline, Collegeville, PA.
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Jesus R. Medina
1GlaxoSmithKline, Collegeville, PA.
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Arthur Shu
1GlaxoSmithKline, Collegeville, PA.
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William H. Li
1GlaxoSmithKline, Collegeville, PA.
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Yanhong Feng
1GlaxoSmithKline, Collegeville, PA.
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M. Phillip DeYoung
1GlaxoSmithKline, Collegeville, PA.
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Christine M. Gardiner
1GlaxoSmithKline, Collegeville, PA.
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Antony R. Chadderton
1GlaxoSmithKline, Collegeville, PA.
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Melissa Dumble
1GlaxoSmithKline, Collegeville, PA.
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Qi Liu
1GlaxoSmithKline, Collegeville, PA.
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Sridhar Rabindran
1GlaxoSmithKline, Collegeville, PA.
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DOI: 10.1158/1538-7445.AM10-LB-116 Published April 2010
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Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Abstract

Phosphoinositide-dependent protein kinase-1 (PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway which is the most commonly deregulated signaling pathway across all cancers. In vivo studies have shown that AKT, p70S6K, RSK and protein kinase C are key mediators of PDK1 function, regulating diverse cellular processes. Activation of these substrates by PDK1 leads to an increase in glucose uptake, protein synthesis, and inhibition of pro-apoptotic proteins. Conversely, knockdown of PDK1 protein levels in tumor cells leads to decreased tumor cell proliferation and increased apoptosis. Furthermore, a hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN+/- mice. Taken together, these observations suggest that an inhibitor of PDK1 could be beneficial in treating cancer. Therefore, we initiated a medicinal chemistry program to discover PDK1 inhibitors as potential anticancer agents.

We have identified an aminoindazole PDK1 inhibitor, GSK2334470, derived from a fragment screening hit which we optimized using structure-based design and PDK1 protein crystallography. Potency and kinase selectivity were attributed to key interactions within the ATP binding site between the inhibitor and the back pocket and glycine-rich loop of PDK1. GSK2334470 is a potent inhibitor of PDK1 kinase (IC50 = 0.5 nM) with a high level of specificity for PDK1 based on test results from in an in vitro kinase selectivity panel of more than 280 kinases. In PC-3 cells, GSK2334470 effectively inhibited phosphorylation of AKTT308 (IC50 = 113 nM) and RSKS221 (IC50 = 293 nM) but not AKTS473 (IC50 > 30,000 nM). These results are consistent with the high specificity of GSK2334470 for PDK1 inhibition. In a panel of approximately 300 cell lines, GSK2334470 demonstrated modest antiproliferative activity overall, with low micromolar activity seen in several breast cancer cell lines and in a variety of hematological cancer cells. Interestingly, GSK2334470 displayed sub-micromolar antiproliferative activity against AML cell lines that are clinically classified as M4 and M5 FAB-subtypes. Therefore, we evaluated the pharmacodynamics of GSK2334470 in mice implanted with OCI-AML2 xenografts. GSK2334470 dosed i.p. at 100 mg/kg resulted in 58 and 29% inhibition of AKTT308 phosphorylation at 3 and 6 h, respectively and 57 and 71% inhibition of RSKS221 phosphorylation at 3 and 6 h, respectively. There was no observed change on AKTS473 phosphorylation. Our results demonstrate that GSK23334470 is a potent, highly selective PDK1 inhibitor which can decrease PDK1 signaling in a tumor xenograft model.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-116.

  • ©2010 American Association for Cancer Research
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Cancer Research: 70 (8 Supplement)
April 2010
Volume 70, Issue 8 Supplement
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Abstract LB-116: GSK2334470: A potent and highly selective inhibitor of PDK1
Jeffrey M. Axten, Jesus R. Medina, Arthur Shu, William H. Li, Yanhong Feng, M. Phillip DeYoung, Christine M. Gardiner, Antony R. Chadderton, Melissa Dumble, Qi Liu and Sridhar Rabindran
Cancer Res April 15 2010 (70) (8 Supplement) LB-116; DOI: 10.1158/1538-7445.AM10-LB-116

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Abstract LB-116: GSK2334470: A potent and highly selective inhibitor of PDK1
Jeffrey M. Axten, Jesus R. Medina, Arthur Shu, William H. Li, Yanhong Feng, M. Phillip DeYoung, Christine M. Gardiner, Antony R. Chadderton, Melissa Dumble, Qi Liu and Sridhar Rabindran
Cancer Res April 15 2010 (70) (8 Supplement) LB-116; DOI: 10.1158/1538-7445.AM10-LB-116
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Cancer Research Online ISSN: 1538-7445
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