Psf1 Inhibitors

Chemical inhibitors of Psf1 can interfere with its role in DNA replication initiation and progression through various mechanisms. Aphidicolin, for instance, selectively targets DNA polymerase alpha and delta, crucial for the DNA synthesis that Psf1 facilitates as part of the GINS complex. By inhibiting these polymerases, aphidicolin directly prevents the replication fork's progression, thereby inhibiting Psf1's function. Similarly, camptothecin and etoposide, through their inhibition of topoisomerase I and II respectively, induce DNA breaks and impede DNA unwinding and synthesis. The resulting DNA damage and the prevention of supercoil relaxation indirectly inhibit Psf1 by disrupting the replication fork's smooth advancement, which Psf1 is integral to. Mitoxantrone contributes to this effect by intercalating with DNA and halting topoisomerase II activity, further inhibiting DNA replication and transcription processes that Psf1 is essential for.

Compounds such as hydroxyurea and gemcitabine disrupt the supply and integrity of the DNA building blocks. Hydroxyurea depletes deoxyribonucleotide pools by inhibiting ribonucleotide reductase, while gemcitabine incorporates itself into DNA, causing chain termination. Both actions lead to a compromised DNA replication process, functionally inhibiting Psf1's activity in initiating this fundamental cellular process. Cytarabine's incorporation into DNA similarly interrupts DNA replication, which would indirectly inhibit Psf1. Palbociclib and flavopiridol target the cell cycle machinery; by inhibiting CDK4/6 and CDK1 respectively, they cause cell cycle arrest, thereby preventing Psf1 from engaging in its role during DNA replication initiation. Thioguanine, trifluridine, and clofarabine also target DNA synthesis and integrity but through different mechanisms. Thioguanine and trifluridine get incorporated into DNA, leading to dysfunctional replication, while clofarabine inhibits both ribonucleotide reductase and DNA polymerases, further impeding DNA synthesis. These disruptions to DNA integrity and synthesis all serve to indirectly inhibit the functional role of Psf1 in the DNA replication process.