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

    Year: 2022

    Journal: Biomedicines, Volume 10, AUG

    Authors: Pauzaite, Tekle; Tollitt, James; Sopaci, Betul; Caprani, Louise; Iwanowytsch, Olivia; Thacker, Urvi; Hardy, John G.; Allinson, Sarah L.; Copeland, Nikki A.

    Organizations: NWCR [CR1079, CD2020.21]; JoyWelch Education charity trust; Lancaster University FHM studentship; Turkish scientific and technological research council (TUBITAK)

    Keywords: DNA replication; Dbf4-dependent kinase (DDK); chemical probes; kinase inhibition; RB+ cancer

    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.
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