PUBLICATION
Illuminating a Dark Kinase: Structure-Guided Design, Synthesis, and Evaluation of a Potent Nek1 Inhibitor and Its Effects on the Embryonic Zebrafish Pronephros
- Authors
- Baumann, G., Meckel, T., Böhm, K., Shih, Y.H., Dickhaut, M., Reichardt, T., Pilakowski, J., Pehl, U., Schmidt, B.
- ID
- ZDB-PUB-220128-1
- Date
- 2022
- Source
- Journal of medicinal chemistry 65: 1265-1282 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Drug Design*
- Embryo, Nonmammalian/drug effects*
- Embryo, Nonmammalian/enzymology
- NIMA-Related Kinase 1/antagonists & inhibitors*
- Polycystic Kidney Diseases/drug therapy*
- Polycystic Kidney Diseases/enzymology
- Polycystic Kidney Diseases/pathology
- Pronephros/drug effects*
- Pronephros/embryology
- Pronephros/enzymology
- Protein Kinase Inhibitors/chemical synthesis*
- Protein Kinase Inhibitors/pharmacology*
- Zebrafish
- PubMed
- 35081715 Full text @ J. Med. Chem.
Citation
Baumann, G., Meckel, T., Böhm, K., Shih, Y.H., Dickhaut, M., Reichardt, T., Pilakowski, J., Pehl, U., Schmidt, B. (2022) Illuminating a Dark Kinase: Structure-Guided Design, Synthesis, and Evaluation of a Potent Nek1 Inhibitor and Its Effects on the Embryonic Zebrafish Pronephros. Journal of medicinal chemistry. 65:1265-1282.
Abstract
NIMA-related kinase 1 (Nek1) has lately garnered attention for its widespread function in ciliogenesis, apoptosis, and the DNA-damage response. Despite its involvement in various diseases and its potential as a cancer drug target, no directed medicinal chemistry efforts toward inhibitors against this dark kinase are published. Here, we report the structure-guided design of a potent small-molecule Nek1 inhibitor, starting from a scaffold identified by kinase cross-screening analysis. Seven lead compounds were identified in silico and evaluated for their inhibitory activity. The top compound, 10f, was further profiled for efficacy, toxicity, and bioavailability in a zebrafish polycystic kidney disease model. Administration of 10f caused the expansion of fluorescence-labeled proximal convoluted tubules, supporting our hypothesis that Nek1-inhibition causes cystic kidneys in zebrafish embryos. Compound 10f displayed insignificant inhibition in 48 of 50 kinases in a selectivity test panel. The findings provide a powerful tool to further elucidate the function and pharmacology of this neglected kinase.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping