Helleday lab on track to novel potent OGG1 inhibitors

Inhibition of OGG1 – new anti-inflammatory treatment

We are introducing a completely new approach for treatment of inflammatory diseases based on the cross-sectional research areas of DNA repair and inflammation. We have demonstrated proof of principle showing that therapeutic treatment with our tool compound, an OGG1 inhibitor, TH5487 significantly reduces the inflammation in mice with lung inflammation.

Upon exposure to inflammatory agents, receptor-ligand interactions in cells cause an elevation of reactive oxygen species (ROS) and DNA damage. The pro-inflammatory immune cells that drive auto-immunity and inflammation suffer from high level of oxidative stress and therefore require specific detoxification enzymes for survival and function. One enzyme of specific interest is OGG1, 8-oxo guanine DNA glycosylase 1. Through binding to promoter regions, enriched in oxidized guanines, this enzyme recruits other proteins such as transcription factors, e.g. NF-ƘB to form complexes, promoting transcription of pro-inflammatory genes. Our OGG1 inhibitor TH5487 prevents OGG1 from binding to DNA and thereby dampening the inflammatory responses in animal models.

For more information about the mechanism of action please refer to the original publication.

We are advancing our leading science on the OGG1 pathway to develop novel therapies for severe lung inflammation diseases with large medical need such as ARDS, COPD, severe non allergic asthma and idiopathic pulmonary fibrosis (IPF).

The Helledaylab is also open for collaborations and partnership to enable development of OGG1 inhibitors as potential antiinflammatory therapies. Please contact Thomas Helleday directly at thomas.helleday@scilifelab.se for further information.

Left: Gallery illustrating the binding mode of 8-oxoguanine modified double stranded DNA to OGG1 (PDB: 1EBM); red to blue color coding of the OGG1 protein indicates a strong positive electrostatic potential of the binding site (blue = positive, red = negative); Later the gallery shows the crystal structure of OGG1 with TH5675, confirming targeting of the positively charged active site; Right: A video generated to demonstrate inhibitor binding and replacement of DNA as a ligand.

Lead generation of OGG1 inhibitors beyond TH5487

Initially, CBK149850 (45% inhibition at 10 µM) was identified as a starting point for lead generation from a high-throughput screen of 17,940 compounds. Interrogation of the structure-activity relationships (SARs) by systematic modification of CBK149850 yielded TH5487 as an initial lead molecule. While substantially more potent (IC50 = 342 nM), obtaining co-crystal structures proved very challenging, due to the limited solubility of both the inhibitors and the protein construct used. In the absence of adequate structural information the SAR of TH5487 was further explored, and collectively over 700 structural analogues were synthesized and tested biochemically. A real breakthrough came when a crystal structure was obtained of mouse OGG1 in complex with TH5675. The mouse homologue of OGG1 has a nearly identical active site but is more soluble due to solubilizing mutations at the protein surface. Furthermore, changing from TH5487 to the less potent but substantially more soluble TH5675 yielded crystals clearly showing bound ligand in the protein active site. To our surprise TH5675 bound with the hydrophobic p-iodophenyl moiety inserted deeply into the 8-oxoguanine pocket, while the benzimidazolone moiety was oriented outward and partially solvent-exposed. With this detailed atomic map at hand, tailored modifications could be made to further improve solubility and metabolic stability while simultaneously improving potency to low nanomolar digits and below. This is illustrated in the figures of the gallery on the left side, where a representative set of OGG1 inhibitors from the TH5487 series are showing progression from TH5487 towards optimal lipophilic ligand efficiency (LLE*) as indicated by the blue region. The second figure further demonstrates the benefits of structure based drug design, as compounds of the TH5487 series synthesized after access to the high resolution crystal structure are highlighted in green and those from before in red.

* for a review see: Leeson PD, Empfield JR (2010) Reducing the Risk of Drug Attrition Associated with Physicochemical Properties. Annu Rev Med Chem 45, 393-407.

This work was funded by the National Institute of Allergic and Infectious Diseases NIAID/AI062885 (I.B.), The Faculty of Medicine at the Norwegian University of Science and Technology and the Central Norway Regional Health Authority (A.S. and H.E.K., project no. 46056921), Svanhild and Arne Musts Fund for Medical Research (A.S. and H.E.K.), Vinnova (A.C.-K and T.H.), the European Unions Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 722729 (B.M.F.H. and T.H.), the European Research Council (T.H. TAROX Programme), The Knut and Alice Wallenberg Foundation and the Swedish Foundation for Strategic Research (T.H. and P.S.), Swedish Research Council (T.H. and P.S.), Swedish Cancer Society (T.H. and P.S.), the Swedish Childrens Cancer Foundation (T.H.), the Swedish Pain Relief Foundation (T.H.), and the Torsten and Ragnar Söderberg Foundation (T.H.).

 

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