Development and Characterization of new Inhibitors for Protein Kinase Nek1

• Main Author: Baumann, Georg
• Format: Others
• Language: en
• Published: 2021
• Online Access: https://tuprints.ulb.tu-darmstadt.de/19159/1/GBaumann_Dissertation_%20Farbe_Doppelseitig.pdf; Baumann, Georg <http://tuprints.ulb.tu-darmstadt.de/view/person/Baumann=3AGeorg=3A=3A.html> (2021):Development and Characterization of new Inhibitors for Protein Kinase Nek1. (Publisher's Version)Darmstadt, Technische Universität, DOI: 10.26083/tuprints-00019159 <https://doi.org/10.26083/tuprints-00019159>, [Ph.D. Thesis]

Despite the impressive accomplishments in the development of small molecule kinase inhibitors over the past 25 years, the majority of human kinases still lack high-quality inhibitors that can be used as chemical probes to investigate their biological function and pharmacology. Many members of the untargeted kinome are known to play a crucial role in the cell cycle and thus represent unexploited cancer drug targets. NIMA-related kinase 1 (Nek1) is one such example, which has lately gained attention for its widespread function in ciliogenesis, apoptosis, and the DNA-damage response and is involved in numerous cancers and several ciliopathies, and neurodegenerative diseases. This work reports the development of the first selective high-quality tool compounds for Nek1 inhibition using structure-guided medicinal chemistry methods. In the first step, two novel 7 azaindole scaffolds were derived from published structural data and reported kinome cross-screening analyses. Iterative steps of computer-assisted design, synthesis, and evaluation of structure-activity-relationships then led to the identification of seven lead compounds, and the top compound was further profiled for its in vivo efficacy, toxicity, and bioavailability in a self-established zebrafish polycystic kidney disease model. Administration of the top compound caused the quantifiable expansion of fluorescence-labeled proximal convoluted tubules, thus supporting the hypothesis that Nek1-inhibition causes cystic kidneys in zebrafish embryos. The methods used provide a blueprint for the fast and resource-efficient development of chemical probes for other dark kinases from widely available chemogenomic kinase data sets.