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BIOTEK2021-Bioteknologi for verdiskaping

Optimalisering: Optimization of novel CSF1R inhibitors - New drugs for osteoporosis

Alternative title: Optimalisering av nye CSF1R inhibitorer - Nye medisiner mot benskjørhet

Awarded: NOK 7.7 mill.

During the project period, more than 350 new molecules intended as inhibitors of the receptor enzyme CSF1R have been prepared and characterized. Successful inhibition of this receptor may, among other things, have an effect in patients with osteoporosis. The effect of all molecules produced was tested against the enzyme in question and more than 100 molecules were found to be so active that they were further tested. One of the most active molecules was crystallized together with the enzyme and the structure of the complex was examined by X-ray diffraction. This information was then used for further simulations and computer modeling of possible interactions between the active molecules and the protein. This knowledge was again used to further develop the active molecules to become even better, water-soluble and active binders. The most active molecules were then tested in genetically modified cells specifically designed to respond to the specific inhibitors. Since the compounds are intended as a possible medicine for osteoporosis, we have also tested the optimized substances on human "bone-eating" osteoclast cells and saw a good effect. Furthermore, we have controlled the stability and toxicity of these compounds in rats and mice. The effect of the best drugs has been tested on control cells in mice and they show a very good effect. Finally, an experiment was done with osteoporetic rats and mice, but the results from these experiments are unfortunately not finished by the end of the project. The project has nevertheless been so successful that we have succeeded with funding from a European investment company that we will co-finance the project for the next three years.

Flere inhibitorer med god in vivo aktivitet er fremstilt. Etter demonstrasjon av vellykket proof-of-concept i en ostoporose sykdomsmodell vil man potensielt kunne starte en klinisk fase i denne legemiddelutviklingen.

Signaling via the tyrosine kinase transmembrane receptor CSF1R is crucial for the differentiation, proliferation and survival of macrophages. Targeting this receptor to modulate macrophage populations may result in therapeutic effects in several types of clinical diseases such as inflammatory diseases, cancer, autoimmunity, and bone diseases. This potentially new treatment is currently being pursued by several big pharma companies for cancer applications, however, there is no CSF1R inhibitor approved by US Food and Drug Administration (FDA) to date. The organic chemists Eirik Sundby and Bård Hoff (NTNU) have for years designed and synthesized low molecular weight compounds to identify novel tyrosine kinase inhibitors. Our recent, unpublished results demonstrate that these novel inhibitors efficiently and selectively inhibit CSF1R signaling in a model cell system . Here, we propose to optimize novel drug leads into molecules that would be potential osteoporosis drugs for major pharma-companies. In order to reach this goal, we have initiated a highly synergistic consortium consisting of experts in medicinal chemistry, in silico modelling and drug development (Eirik Sundby/Bård Hoff), in vitro inhibitor assays development and in vivo studies (Geir Bjørkøy), CSF1R and animal phenotypes (Claire Pridans, Edinburgh), and osteoporosis (Unni Syversen, St.Olav). Finally, in order to guide us in the drug development phase, we have formalised a collaboration with Lead Discovery Center (Bert Klebl) GmbH, Dortmund (a part of Max Planck Innovation). At the end of the project period, we intend to deliver 2-3 lead compounds which either should be ready for further licensing to commercial partners, for a start-up company or, if needed, to be the basis for an application to FORNY2020.

Funding scheme:

BIOTEK2021-Bioteknologi for verdiskaping