Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation

Abstract

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice.TH5487 prevents tumor necrosis factor-α-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.

c-Abl–Mediated Tyrosine Phosphorylation of PARP1 Is Crucial for Expression of Proinflammatory Genes

“…Randomly selected fields were photographed using an OLYMPUS Microscope System BX53P microscope with a built-in digital charge-coupled device color camera, DP73WDR. In parallel experiments, lung tissue sections were processed for staining with H&E to identify neutrophils in lung sections as we published previously (39). Randomly, five fields of each sample were captured at a magnification of 3160 using a CoolSNAP HQ2 camera mounted on a Nikon Eclipse Ti microscope.…”

Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates Methotrexate anticancer effects

“…The separated cells (at least 1×10 6 cells from each sorted population) were collected in tubes containing 0.5 ml culture medium and after centrifugation, cell pellets were stored at -20ºC until used for DNA or protein extraction. We have adapted the telomere oxidation protocol previously described (25) to quantify the relative accumulation of oxidized bases in specific genome regions by incubating the DNA with hOGG1protein, which was previously purified as previously reported (23). This is a qPCR method which is based on differences in PCR kinetics between template DNA digested by OGG1 and undigested DNA.…”

“…The recently developed OGG1 inhibitor TH5487 has proven to bind efficiently to the catalytic site of OGG1 blocking its enzymatic activity (23). We hypothesized that OGG1 inhibition may recapture the phenotypic telomeric defects previously observed in OGG1 depleted cells (16), representing an attractive and unexplored opportunity for compromising telomere integrity in cells exposed to high ROS levels.…”

“…Recently, the first example of cell-active inhibitors targeting OGG1 has been reported (23). Also details on how TH5487 binds to the human OGG1 sensitizing cancer cell lines by inducing replication stress without increasing nuclear 8oxoG levels (T. Visnes, under review).…”

“…Methotrexate as a combination partner of TNF inhibitors induces high remission rates of rheumatoid arthritis (52) or superior drug survival in psoriatic arthrosis 19 patients receiving methotrexate co-medication with TNF-inhibitor (53). In this regard TH5487 is also known to prevent tumor necrosis factor-α-induced OGG1-DNA interactions that mediate TNF related proinflammatory gene expression (23). Hence, considering TH5487 as a "TNF-like inhibitor" we could expect some advantages of combination therapies in autoimmune diseases as well.…”