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

不受调节的细胞增殖是癌症的标志，并且通常通过用DNA烷化剂（例如顺铂）、抗代谢物（例如培美曲塞）或抗肿瘤抗生素（例如多柔比星）形式的DNA损伤试剂抑制DNA合成来治疗。这些化疗药物在杀死癌细胞方面非常有效，但它们也产生大量的DNA突变，增加复发的机会，并且同样影响健康细胞，导致不利的副作用。因此，需要开发具有改进的特性和较少副作用的新型DNA合成抑制剂。一个令人兴奋的替代方法是抑制DNA复制机制的形成，确保DNA本身不被损坏。DNA复制受到高度调控，以确保DNA不会复制超过一次。一个关键的组成部分是加载因子Cdt 1，这是染色质结合的微型染色体维持（MCM 2 -7）复合物所需的。Cdt 1蛋白水平必须在细胞周期中严格调节，以防止不受控制的复制叉组装和DNA的再复制。至关重要的是，健康细胞具有检查点以确保正确的起源许可，而癌细胞没有，并且已经显示通过稳定的双生蛋白衍生物的过表达抑制起源许可导致癌细胞中不成功的有丝分裂和p53非依赖性细胞死亡。该项目将开发作为Cdt 1抑制剂的钉合肽Geminin模拟物，以阻止起源许可并诱导癌细胞凋亡。

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.