Synthesis and Pharmacological Development of Pyrrolopyrimidines and Purines as Inhibitors of the Colony Stimulating Factor 1 Receptor Tyrosine Kinase
Doctoral thesis
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https://hdl.handle.net/11250/3080411Utgivelsesdato
2023Metadata
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- Institutt for kjemi [1389]
Sammendrag
Protein kinases regulate the function of virtually all fundamental cellular processes and have thus become important drug targets for modulating abnormal cellular behavior in a variety of disease states. However, the ubiquitous and conserved nature of protein kinases poses a considerable challenge in the development of selective drugs with constrained biological effects that are suitable in therapeutic settings. In the last years, major strides toward a more comprehensive understanding of kinase structure and function have led to an explosion in the number of kinase-inhibiting drugs, and new druggable protein kinases are continuously uncovered. In particular, the colony-stimulating factor 1 receptor (CSF1R) protein kinase has emerged as an attractive target. Due to the key regulatory role of CSF1R in myeloid lineage cells, therapies that target the protein have significant potential in the treatment of disorders where aberrant myeloid cells are implicated, such as cancers, dementia, and osteoporosis.
In this work, a series of pyrrolo[2,3-d]pyrimidine- and purine-based inhibitors of CSF1R have been synthesized and subsequently assayed in relevant biological experiments. The bulk of the inhibitors were synthesized from pyrrolo[2,3-d]pyrimidine and purine core scaffolds dihalogenated on the analogous positions C- 4/C-6 and C-6/C-8. The halogens served as chemical handles for the attachment of appropriate substituents through nucleophilic aromatic substitution and palladium- catalyzed cross-coupling chemistry. The heterocyclic scaffolds were protected on the free N-H groups during attachment of the substituents, and deprotected in the last step to yield the final inhibitors.
Evaluation of the inhibitors to determine their suitability as small-molecule drugs was carried out using a range of experiments. First-line assessment of the inhibitors was based on enzyme-level inhibition, which was used to guide the initial synthetic direction of the project. From this work, a structure–activity relationship was established, and numerous inhibitors more potent than reference drug pexidartinib were identified. X-ray determination of a protein–ligand cocrystal, full-scale kinase panel screens, and profiling of enzyme activation states revealed a series of remarkably selective CSF1R inhibitors with atypical binding behavior. In vitro ADME profiling, cell-based assays, and pharmacokinetic studies in animals finally demonstrated a class of compounds with a multitude of favorable drug characteristics, and a solid foundation for further drug development.