Illuminating a Dark Kinase: Structure-Guided Design, Synthesis, and Evaluation of a Potent Nek1 Inhibitor and Its Effects on the Embryonic Zebrafish Pronephros

• Published in: Journal of medicinal chemistry Vol. 65; no. 2; pp. 1265 - 1282
• Main Authors: Baumann, Georg, Meckel, Tobias, Böhm, Kevin, Shih, Yung-Hsin, Dickhaut, Mirco, Reichardt, Torben, Pilakowski, Johannes, Pehl, Ulrich, Schmidt, Boris
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.01.2022; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Drug Design; Embryo, Nonmammalian - drug effects; Embryo, Nonmammalian - enzymology; Life Sciences & Biomedicine; NIMA-Related Kinase 1 - antagonists & inhibitors; Pharmacology & Pharmacy; 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; Science & Technology; Zebrafish; PATHWAYS; OVEREXPRESSION; PHOSPHORYLATION; POLYCYSTIC KIDNEY-DISEASE; DNA-DAMAGE RESPONSE; PROTEIN-KINASE; MUTATIONS; IDENTIFICATION; EXPRESSION; CELL-DEATH
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c02118

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.