Design of potent and selective hybrid inhibitors of the mitotic kinase Nek2: structure-activity relationship, structural biology, and cellular activity.

Paolo Innocenti,Kathy Boxall,Richard Bayliss,Andrew M Fry,Corine Mas-Droux,G Wynne Aherne,Kwai-Ming J Cheung,Maura Westlake,Joanne E Baxter,Swen Hoelder,Lisa Pickard,Tara Hardy,Sharon Yeoh,Fiona Rowan,Savade Solanki

doi:10.1021/jm201683b

Paolo Innocenti, Kathy Boxall + Show 13 more

Open Access

https://doi.org/10.1021/jm201683b

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Abstract

We report herein a series of Nek2 inhibitors based on an aminopyridine scaffold. These compounds have been designed by combining key elements of two previously discovered chemical series. Structure based design led to aminopyridine (R)-21, a potent and selective inhibitor able to modulate Nek2 activity in cells.

Highlights

We report a series of Nek[2] inhibitors based on an aminopyridine scaffold
Our results indicated that the poor ligand efficiency (LE) and modest potency of these compounds were at least in part due to inefficient binding of the phenyl substituted benzimidazole core 4 (IC50 value of 62 μM, LE = 0.32, Figure 1)
A replacement candidate for the benzimidazole moiety was the aminopyrazinetype scaffold, which in our studies consistently showed better LE compared to the benzimidazoles

Summary

Introduction

We report a series of Nek[2] inhibitors based on an aminopyridine scaffold. These compounds have been designed by combining key elements of two previously discovered chemical series. The resulting hybrid 11a showed a Nek[2] IC50 value of 0.79 μM (Table 1) and proved to be approximately equipotent to the parent compounds (0.23 μM and 0.36 μM, respectively, for pyrazine 2 and benzimidazole (R)-3, Figure 1).

Results

Conclusion