Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

Abstract

Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues together with aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to treat underlying causes of disease. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, a novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF.

Targeting the DNA repair enzymes MTH1 and OGG1 as a novel approach to treat inflammatory diseases

“…In addition to acute pneumonia induced by LPS or TNF‐α, emerging data suggest that OGG1 inhibition by TH5487 attenuates lung fibrosis in a bleomycin model of pulmonary fibrosis 43 . This could indicate that also chronic inflammation can be mitigated by OGG1 inhibition.…”

“…In addition to acute pneumonia induced by LPS or TNF-α, emerging data suggest that OGG1 inhibition by TH5487 attenuates lung fibrosis in a bleomycin model of pulmonary fibrosis. 43 This could indicate that also chronic inflammation can be mitigated by OGG1 inhibition. One challenge with immunosuppression in the context of both acute and chronic inflammation is that the immunosuppression itself can have adverse effects.…”

“…In the bleomycin and LPS/TNF-α models, no infectious agent was used, and so a comparable effect of antiinflammatory drugs like dexamethasone would have been expected, which was also demonstrated with preliminary data. 8,43 However, albeit being indispensable anti-inflammatory drugs, corticosteroids impose severe risks of opportunistic or exacerbated infections and have long been considered controversial in the context of acute infectious inflammation, like sepsis. 45,46 One important consequence of corticosteroids is the disadvantageous effect on T cells, where dexamethasone suppresses T cell proliferation and differentiation.…”

8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury

“…The first evidence implicating OGG1 in fibrotic gene activation came from whole transcriptome analysis, where we found that OGG1-BER-driven signaling triggers airway remodeling programs ( 25 , 26 ). Administration of the OGG1 inhibitor, TH5487, which displaces 8-oxoG from the active binding site of OGG1, decreased tissue remodeling and bleomycin-induced pulmonary fibrosis in murine models ( 27 , 28 ). However, the mechanism of transcriptional reprogramming orchestrated by 8-oxoG-OGG1 complex in fibrotic gene activation remains poorly understood.…”

Optimization of N‐Piperidinyl‐Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8‐Oxo‐Guanine DNA Glycosylase 1

“…[4,5] We and others have developed potent OGG1 inhibitors which delay lung inflammation in rodent models of disease. [6][7][8] In addition, extensive data has been published on the cellular effects of OGG1 inhibitors in preclinical cancer models. [9][10][11][12] Consequently, the tool compound TH5487 has been applied in a number of studies.…”