A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity

Alessia Montagnoli; Barbara Valsasina; Valter Croci; Maria Menichincheri; Sonia Rainoldi; Vanessa Marchesi; Marcello Tibolla; Pierluigi Tenca; Deborah Brotherton; Clara Albanese; Veronica Patton; Rachele Alzani; Antonella Ciavolella; Francesco Sola; Antonio Molinari; Daniele Volpi; Nilla Avanzi; Francesco Fiorentini; Marina Cattoni; Sandra Healy; Dario Ballinari; Enrico Pesenti; Antonella Isacchi; Jurgen Moll; Aaron Bensimon; Ermes Vanotti; Corrado Santocanale

doi:10.1038/nchembio.90

A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity

Alessia Montagnoli, Barbara Valsasina, Valter Croci, Maria Menichincheri, Sonia Rainoldi, Vanessa Marchesi, Marcello Tibolla, Pierluigi Tenca, Deborah Brotherton, Clara Albanese, Veronica Patton, Rachele Alzani, Antonella Ciavolella, Francesco Sola, Antonio Molinari, Daniele Volpi, Nilla Avanzi, Francesco Fiorentini, Marina Cattoni, Sandra HealyDario Ballinari, Enrico Pesenti, Antonella Isacchi, Jurgen Moll, Aaron Bensimon, Ermes Vanotti, Corrado Santocanale

Molecular Biosciences

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

179 Citations (Scopus)

Abstract

Cdc7 is an essential kinase that promotes DNA replication by activating origins of replication. Here, we characterized the potent Cdc7 inhibitor PHA-767491 (1) in biochemical and cell-based assays, and we tested its antitumor activity in rodents. We found that the compound blocks DNA synthesis and affects the phosphorylation of the replicative DNA helicase at Cdc7-dependent phosphorylation sites. Unlike current DNA synthesis inhibitors, PHA-767491 prevents the activation of replication origins but does not impede replication fork progression, and it does not trigger a sustained DNA damage response. Treatment with PHA-767491 results in apoptotic cell death in multiple cancer cell types and tumor growth inhibition in preclinical cancer models. To our knowledge, PHA-767491 is the first molecule that directly affects the mechanisms controlling initiation as opposed to elongation in DNA replication, and its activities suggest that Cdc7 kinase inhibition could be a new strategy for the development of anticancer therapeutics.

Original language	English
Pages (from-to)	357-365
Number of pages	9
Journal	Nature Chemical Biology
Volume	4
Issue number	6
DOIs	https://doi.org/10.1038/nchembio.90
Publication status	Published - Jun 2008

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Montagnoli, A., Valsasina, B., Croci, V., Menichincheri, M., Rainoldi, S., Marchesi, V., Tibolla, M., Tenca, P., Brotherton, D., Albanese, C., Patton, V., Alzani, R., Ciavolella, A., Sola, F., Molinari, A., Volpi, D., Avanzi, N., Fiorentini, F., Cattoni, M., ... Santocanale, C. (2008). A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nature Chemical Biology, 4(6), 357-365. https://doi.org/10.1038/nchembio.90

@article{5db50239c7c244daac522883a07b6e30,

title = "A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity",

abstract = "Cdc7 is an essential kinase that promotes DNA replication by activating origins of replication. Here, we characterized the potent Cdc7 inhibitor PHA-767491 (1) in biochemical and cell-based assays, and we tested its antitumor activity in rodents. We found that the compound blocks DNA synthesis and affects the phosphorylation of the replicative DNA helicase at Cdc7-dependent phosphorylation sites. Unlike current DNA synthesis inhibitors, PHA-767491 prevents the activation of replication origins but does not impede replication fork progression, and it does not trigger a sustained DNA damage response. Treatment with PHA-767491 results in apoptotic cell death in multiple cancer cell types and tumor growth inhibition in preclinical cancer models. To our knowledge, PHA-767491 is the first molecule that directly affects the mechanisms controlling initiation as opposed to elongation in DNA replication, and its activities suggest that Cdc7 kinase inhibition could be a new strategy for the development of anticancer therapeutics.",

author = "Alessia Montagnoli and Barbara Valsasina and Valter Croci and Maria Menichincheri and Sonia Rainoldi and Vanessa Marchesi and Marcello Tibolla and Pierluigi Tenca and Deborah Brotherton and Clara Albanese and Veronica Patton and Rachele Alzani and Antonella Ciavolella and Francesco Sola and Antonio Molinari and Daniele Volpi and Nilla Avanzi and Francesco Fiorentini and Marina Cattoni and Sandra Healy and Dario Ballinari and Enrico Pesenti and Antonella Isacchi and Jurgen Moll and Aaron Bensimon and Ermes Vanotti and Corrado Santocanale",

year = "2008",

month = jun,

doi = "10.1038/nchembio.90",

language = "English",

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pages = "357--365",

journal = "Nature Chemical Biology",

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Montagnoli, A, Valsasina, B, Croci, V, Menichincheri, M, Rainoldi, S, Marchesi, V, Tibolla, M, Tenca, P, Brotherton, D, Albanese, C, Patton, V, Alzani, R, Ciavolella, A, Sola, F, Molinari, A, Volpi, D, Avanzi, N, Fiorentini, F, Cattoni, M, Healy, S, Ballinari, D, Pesenti, E, Isacchi, A, Moll, J, Bensimon, A, Vanotti, E & Santocanale, C 2008, 'A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity', Nature Chemical Biology, vol. 4, no. 6, pp. 357-365. https://doi.org/10.1038/nchembio.90

TY - JOUR

T1 - A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity

AU - Montagnoli, Alessia

AU - Valsasina, Barbara

AU - Croci, Valter

AU - Menichincheri, Maria

AU - Rainoldi, Sonia

AU - Marchesi, Vanessa

AU - Tibolla, Marcello

AU - Tenca, Pierluigi

AU - Brotherton, Deborah

AU - Albanese, Clara

AU - Patton, Veronica

AU - Alzani, Rachele

AU - Ciavolella, Antonella

AU - Sola, Francesco

AU - Molinari, Antonio

AU - Volpi, Daniele

AU - Avanzi, Nilla

AU - Fiorentini, Francesco

AU - Cattoni, Marina

AU - Healy, Sandra

AU - Ballinari, Dario

AU - Pesenti, Enrico

AU - Isacchi, Antonella

AU - Moll, Jurgen

AU - Bensimon, Aaron

AU - Vanotti, Ermes

AU - Santocanale, Corrado

PY - 2008/6

Y1 - 2008/6

N2 - Cdc7 is an essential kinase that promotes DNA replication by activating origins of replication. Here, we characterized the potent Cdc7 inhibitor PHA-767491 (1) in biochemical and cell-based assays, and we tested its antitumor activity in rodents. We found that the compound blocks DNA synthesis and affects the phosphorylation of the replicative DNA helicase at Cdc7-dependent phosphorylation sites. Unlike current DNA synthesis inhibitors, PHA-767491 prevents the activation of replication origins but does not impede replication fork progression, and it does not trigger a sustained DNA damage response. Treatment with PHA-767491 results in apoptotic cell death in multiple cancer cell types and tumor growth inhibition in preclinical cancer models. To our knowledge, PHA-767491 is the first molecule that directly affects the mechanisms controlling initiation as opposed to elongation in DNA replication, and its activities suggest that Cdc7 kinase inhibition could be a new strategy for the development of anticancer therapeutics.

AB - Cdc7 is an essential kinase that promotes DNA replication by activating origins of replication. Here, we characterized the potent Cdc7 inhibitor PHA-767491 (1) in biochemical and cell-based assays, and we tested its antitumor activity in rodents. We found that the compound blocks DNA synthesis and affects the phosphorylation of the replicative DNA helicase at Cdc7-dependent phosphorylation sites. Unlike current DNA synthesis inhibitors, PHA-767491 prevents the activation of replication origins but does not impede replication fork progression, and it does not trigger a sustained DNA damage response. Treatment with PHA-767491 results in apoptotic cell death in multiple cancer cell types and tumor growth inhibition in preclinical cancer models. To our knowledge, PHA-767491 is the first molecule that directly affects the mechanisms controlling initiation as opposed to elongation in DNA replication, and its activities suggest that Cdc7 kinase inhibition could be a new strategy for the development of anticancer therapeutics.

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U2 - 10.1038/nchembio.90

DO - 10.1038/nchembio.90

M3 - Article

SN - 1552-4450

VL - 4

SP - 357

EP - 365

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 6

ER -

A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity

Abstract

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