Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy

Abstract

DNA damage repair plays a key role in maintaining genomic stability and integrity. Flap endonuclease 1 (FEN1) is a core protein in the base excision repair (BER) pathway and participates in Okazaki fragment maturation during DNA replication. Several studies have implicated FEN1 in the regulation of other DNA repair pathways, including homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Abnormal expression or mutation of FEN1 in cells can cause a series of pathological responses, leading to various diseases, including cancers. Moreover, overexpression of FEN1 contributes to drug resistance in several types of cancers. All this supports the hypothesis that FEN1 could be a therapeutic target for cancer treatment. Targeting FEN1 has been verified as an effective strategy in mono or combined treatment of cancer. Small-molecule compounds targeting FEN1 have also been developed and detected in cancer regression. In this review, we summarize the recent development of small-molecule inhibitors targeting FEN1 in recent years, thereby expanding their therapeutic potential and application.

Down-regulation of DNA key protein-FEN1 inhibits OSCC growth by affecting immunosuppressive phenotypes via IFN-γ/JAK/STAT-1

“… 34 A mouse model carrying an FEN1 mutation that eliminated the FEN1-PCNA interaction was reported in a study, and the DNA breaks caused by this mutation promoted the development of aneuploid cancers. 14 Given the critical role that FEN1 plays in DNA damage repair, we conducted DNA damage-related experiments after downregulating FEN1. As expected, the result showed that FEN1 was positively correlated with PCNA and that the DNA in Cal-27 cells was damaged by knocking down FEN1, which explained the inhibitory effect of FEN1 downregulation in OSCC from the perspective of DNA damage repair.…”

“…10 FEN1 is at the core of cellular DNA metabolism, 11 therefore, studies have mainly focused on DNA metabolism mechanisms, interactions with other proteins and gene mutations. [12][13][14] FEN1 has been shown to be expressed at low levels in quiescent cells but increased in proliferating tissues. 15 This proliferative activityrelated property has also been noted in cancer cells, where FEN1 overexpression has been associated with accelerated progression and shorter survival periods.…”

Distinctive Formation of a DNA–Protein Cross-Link during the Repair of DNA Oxidative Damage: Insights into Human Disease from MD Simulations and QM/MM Calculations

“…MUTYH inherited biallelic variations can result in a condition known as MUTYH-associated polyposis (MAP), which has symptoms including the development of colon polyps and an increased risk of colorectal cancer. − Indeed, an N224S MUTYH variant associated with MAP alters a residue close to the active site, which could cause the reduced catalytic rates that have been linked with the disease . However, this is just one example among over 80 MUTYH missense and truncating variants whose functions are unclear. , There is also evidence that designing novel pharmaceuticals to target enzymes involved in DNA repair pathways may afford successful cancer treatments by increasing the efficacy of anticancer drugs or targeting DNA-repair defective cancers, − and highly specific and potent small molecule inhibitors have already been designed for enzymes that share mechanistic features with DNA glycosylases like MUTYH. − However, to aid the prediction of the dysfunction of MAP-related MUTYH variants in humans and develop possible cancer treatment strategies, the atomic level details of the chemistry facilitated by MUTYH are required. Indeed, structural information has proven essential for the rational development of small-molecule (transition state analogue) inhibitors. − …”

HIV‐1 integrase inhibitor raltegravir promotes DNA damage‐induced apoptosis in multiple myeloma

“…On the other hand, HMGB1 mRNA expression was unchanged in both RPMI 8226 and NCI H929 cells, while its expression was significantly downregulated in raltegravir‐treated U266 cells compared to those with untreated. Furthermore, the mRNA expression of genes involved in NHEJ, such as SETMAR and Ku70, and Fen1, which is involved in base‐excision repair, homologous recombination repair (HRR), and NHEJ (Yang et al, 2022), was observed to have an increasing trend in MM cells treated with raltegravir. Only SETMAR expression was significantly elevated in raltegravir‐treated NCI H929 cells (Figure 4b).…”