AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3Β activation and RNA polymerase II inhibition

L. Santo, S. Vallet, T. Hideshima, D. Cirstea, H. Ikeda, S. Pozzi, K. Patel, Y. Okawa, G. Gorgun, G. Perrone, E. Calabrese, M. Yule, M. Squires, M. Ladetto, M. Boccadoro, P. G. Richardson, N. C. Munshi, K. C. Anderson, N. Raje

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Abstract

Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [3 H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3Β (GSK-3Β) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3Β knockdown restored MM survival, suggesting the involvement of GSK-3Β in AT7519-induced apoptosis. GSK-3Β activation was independent of RNA pol II dephosphorylation confirmed by α-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3Β phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3Β in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM.

Original languageEnglish
Pages (from-to)2325-2336
Number of pages12
JournalOncogene
Volume29
Issue number16
DOIs
Publication statusPublished - Apr 2010

Fingerprint

Glycogen Synthase Kinase 3
Cyclin-Dependent Kinases
RNA Polymerase II
Multiple Myeloma
Apoptosis
Phosphorylation
Amanitins
Cyclins
Uridine
4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide
Small Interfering RNA
Neoplasms
RNA
Growth

Keywords

  • Cyclin-dependent kinase
  • GSK-3b
  • Myeloma
  • RNA pol II

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3Β activation and RNA polymerase II inhibition. / Santo, L.; Vallet, S.; Hideshima, T.; Cirstea, D.; Ikeda, H.; Pozzi, S.; Patel, K.; Okawa, Y.; Gorgun, G.; Perrone, G.; Calabrese, E.; Yule, M.; Squires, M.; Ladetto, M.; Boccadoro, M.; Richardson, P. G.; Munshi, N. C.; Anderson, K. C.; Raje, N.

In: Oncogene, Vol. 29, No. 16, 04.2010, p. 2325-2336.

Research output: Contribution to journalArticle

Santo, L, Vallet, S, Hideshima, T, Cirstea, D, Ikeda, H, Pozzi, S, Patel, K, Okawa, Y, Gorgun, G, Perrone, G, Calabrese, E, Yule, M, Squires, M, Ladetto, M, Boccadoro, M, Richardson, PG, Munshi, NC, Anderson, KC & Raje, N 2010, 'AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3Β activation and RNA polymerase II inhibition', Oncogene, vol. 29, no. 16, pp. 2325-2336. https://doi.org/10.1038/onc.2009.510
Santo, L. ; Vallet, S. ; Hideshima, T. ; Cirstea, D. ; Ikeda, H. ; Pozzi, S. ; Patel, K. ; Okawa, Y. ; Gorgun, G. ; Perrone, G. ; Calabrese, E. ; Yule, M. ; Squires, M. ; Ladetto, M. ; Boccadoro, M. ; Richardson, P. G. ; Munshi, N. C. ; Anderson, K. C. ; Raje, N. / AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3Β activation and RNA polymerase II inhibition. In: Oncogene. 2010 ; Vol. 29, No. 16. pp. 2325-2336.
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abstract = "Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [3 H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3Β (GSK-3Β) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3Β knockdown restored MM survival, suggesting the involvement of GSK-3Β in AT7519-induced apoptosis. GSK-3Β activation was independent of RNA pol II dephosphorylation confirmed by α-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3Β phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3Β in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM.",
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AU - Vallet, S.

AU - Hideshima, T.

AU - Cirstea, D.

AU - Ikeda, H.

AU - Pozzi, S.

AU - Patel, K.

AU - Okawa, Y.

AU - Gorgun, G.

AU - Perrone, G.

AU - Calabrese, E.

AU - Yule, M.

AU - Squires, M.

AU - Ladetto, M.

AU - Boccadoro, M.

AU - Richardson, P. G.

AU - Munshi, N. C.

AU - Anderson, K. C.

AU - Raje, N.

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N2 - Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [3 H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3Β (GSK-3Β) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3Β knockdown restored MM survival, suggesting the involvement of GSK-3Β in AT7519-induced apoptosis. GSK-3Β activation was independent of RNA pol II dephosphorylation confirmed by α-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3Β phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3Β in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM.

AB - Dysregulated cell cycling is a universal hallmark of cancer and is often mediated by abnormal activation of cyclin-dependent kinases (CDKs) and their cyclin partners. Overexpression of individual complexes are reported in multiple myeloma (MM), making them attractive therapeutic targets. In this study, we investigate the preclinical activity of a novel small-molecule multi-CDK inhibitor, AT7519, in MM. We show the anti-MM activity of AT7519 displaying potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [3 H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3Β (GSK-3Β) phosphorylation; conversely pretreatment with a selective GSK-3 inhibitor and shRNA GSK-3Β knockdown restored MM survival, suggesting the involvement of GSK-3Β in AT7519-induced apoptosis. GSK-3Β activation was independent of RNA pol II dephosphorylation confirmed by α-amanitin, a specific RNA pol II inihibitor, showing potent inhibition of RNA pol II phosphorylation without corresponding effects on GSK-3Β phosphorylation. These results offer new insights into the crucial, yet controversial role of GSK-3Β in MM and show significant anti-MM activity of AT7519, providing the rationale for its clinical evaluation in MM.

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