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Biomedicines
Volume 10
Issue 8
10.3390/biomedicines10082012
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Article

Dbf4-Cdc7 (DDK) Inhibitor PHA-767491 Displays Potent Anti-Proliferative Effects via Crosstalk with the CDK2-RB-E2F Pathway

by
Tekle Pauzaite
1,†,
James Tollitt
1,
Betul Sopaci
1,
Louise Caprani
1,
Olivia Iwanowytsch
1,
Urvi Thacker
1,
John G. Hardy
2,3,
Sarah L. Allinson
1 and
Nikki A. Copeland
1,2,*
1
Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK
2
Materials Science Institute, Lancaster University, Lancaster LA1 4YW, UK
3
Department of Chemistry, Faculty of Science and Technology, Lancaster University, Lancaster LA1 4YB, UK
*
Author to whom correspondence should be addressed.
†
Current address: Department of Medicine, Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
Biomedicines 2022, 10(8), 2012; https://doi.org/10.3390/biomedicines10082012
Submission received: 15 July 2022 / Revised: 4 August 2022 / Accepted: 10 August 2022 / Published: 19 August 2022
(This article belongs to the Special Issue Advanced Research of Targeting CDKs in Oncology)
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Abstract

Precise regulation of DNA replication complex assembly requires cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK) activities to activate the replicative helicase complex and initiate DNA replication. Chemical probes have been essential in the molecular analysis of DDK-mediated regulation of MCM2-7 activation and the initiation phase of DNA replication. Here, the inhibitory activity of two distinct DDK inhibitor chemotypes, PHA-767491 and XL-413, were assessed in cell-free and cell-based proliferation assays. PHA-767491 and XL-413 show distinct effects at the level of cellular proliferation, initiation of DNA replication and replisome activity. XL-413 and PHA-767491 both reduce DDK-specific phosphorylation of MCM2 but show differential potency in prevention of S-phase entry. DNA combing and DNA replication assays show that PHA-767491 is a potent inhibitor of the initiation phase of DNA replication but XL413 has weak activity. Importantly, PHA-767491 decreased E2F-mediated transcription of the G1/S regulators cyclin A2, cyclin E1 and cyclin E2, and this effect was independent of CDK9 inhibition. Significantly, the enhanced inhibitory profile of PHA-767491 is mediated by potent inhibition of both DDK and the CDK2-Rb-E2F transcriptional network, that provides the molecular basis for its increased anti-proliferative effects in RB+ cancer cell lines.
Keywords: DNA replication; Dbf4-dependent kinase (DDK); chemical probes; kinase inhibition; RB+ cancer DNA replication; Dbf4-dependent kinase (DDK); chemical probes; kinase inhibition; RB+ cancer

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MDPI and ACS Style

Pauzaite, T.; Tollitt, J.; Sopaci, B.; Caprani, L.; Iwanowytsch, O.; Thacker, U.; Hardy, J.G.; Allinson, S.L.; Copeland, N.A. Dbf4-Cdc7 (DDK) Inhibitor PHA-767491 Displays Potent Anti-Proliferative Effects via Crosstalk with the CDK2-RB-E2F Pathway. Biomedicines 2022, 10, 2012. https://doi.org/10.3390/biomedicines10082012

AMA Style

Pauzaite T, Tollitt J, Sopaci B, Caprani L, Iwanowytsch O, Thacker U, Hardy JG, Allinson SL, Copeland NA. Dbf4-Cdc7 (DDK) Inhibitor PHA-767491 Displays Potent Anti-Proliferative Effects via Crosstalk with the CDK2-RB-E2F Pathway. Biomedicines. 2022; 10(8):2012. https://doi.org/10.3390/biomedicines10082012

Chicago/Turabian Style

Pauzaite, Tekle, James Tollitt, Betul Sopaci, Louise Caprani, Olivia Iwanowytsch, Urvi Thacker, John G. Hardy, Sarah L. Allinson, and Nikki A. Copeland. 2022. "Dbf4-Cdc7 (DDK) Inhibitor PHA-767491 Displays Potent Anti-Proliferative Effects via Crosstalk with the CDK2-RB-E2F Pathway" Biomedicines 10, no. 8: 2012. https://doi.org/10.3390/biomedicines10082012

APA Style

Pauzaite, T., Tollitt, J., Sopaci, B., Caprani, L., Iwanowytsch, O., Thacker, U., Hardy, J. G., Allinson, S. L., & Copeland, N. A. (2022). Dbf4-Cdc7 (DDK) Inhibitor PHA-767491 Displays Potent Anti-Proliferative Effects via Crosstalk with the CDK2-RB-E2F Pathway. Biomedicines, 10(8), 2012. https://doi.org/10.3390/biomedicines10082012

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