Targeting DNA Replication in Cancer: Towards New Therapeutics with Reduced Side Effects

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Unregulated cell proliferation is a hallmark of cancers and it is frequently treated via inhibition of DNA synthesis with DNA damaging reagents in form of DNA alkylating reagents (e.g. cisplatin), antimetabolites (e.g. pemetrexed) or anti-tumor antibiotics (e.g. doxorubicin). These chemotherapeutics are highly efficient at killing cancer cells, but they also generate large numbers of DNA mutations, increasing the chance of relapse and equally affect healthy cells leading to unfavourable side effects.Therefore, there is a need to develop novel DNA synthesis inhibitors with improved characteristics and fewer side effects. An exciting alternative is inhibiting the formation of the DNA replication machinery ensuring the DNA itself is not damaged. DNA replication is highly regulated to guarantee DNA is never replicated more than once. A key component of this is the loading factor Cdt1, which is required for chromatin binding of the mini chromosome maintenance (MCM2-7) complex. Cdt1 protein levels must be tightly regulated during the cell cycle to prevent uncontrolled replication fork assembly and re-replication of DNA. Crucially, healthy cells possess a checkpoint to ensure correct origin licensing whereas cancer cells do not and inhibition of origin licensing via overexpression of a stabilised geminin derivative has been shown to result in unsuccessful mitosis and p53 independent cell death in cancer cells. This project will develop stapled peptide geminin mimics as Cdt1 inhibitors to stall origin licensing and induce apoptosis in cancer cells.