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

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.

Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import

“…Critically, these defects were dependent on the enzymatic activity of the kinase, as we could recapitulate them using a small-molecule NEK1-specific inhibitor (NEK1i) ( P < 0.0001) ( Fig. 3K ) ( 52 ). Together, our findings demonstrate that NEK1 loss of function disrupts TUBA1B homeostasis within neuronal processes and negatively affects downstream processes like neurite regeneration.…”

Pentafluorocyclopropanation of (Hetero)arenes Using Sulfonium Salts: Applications in Late‐Stage Functionalization

“…For example, compound 6 is an IKK2 inhibitor, in which the cyclopropyl unit appended at 2‐position of the pyrrolo[2,3‐ b ]pyridine core plays a key role to enhance potency, selectivity and oral bioavailability in rats [26] . Its pentafluoro derivative 7 and its regioisomer 7′ , bearing the PFCP‐motif in position 3‐, have been synthesized in one step from known 8 [27] following our late‐stage functionalization protocol (Scheme 3).…”