Positioning of an unprecedented spiro[5.5]undeca ring system into kinase inhibitor space

Arramshetti Venkanna,Sang-Yoon Lee,Mahesh K Teli,Mi-Hyun Kim,Bhargav Gupta Nangunuri,Prema Dhorma Lama,Sun Yeou Kim,Lalita Subedi

doi:10.1038/s41598-020-78158-9

Abstract

In-house 1,5-oxaza spiroquinone 1, with spiro[5.5]undeca ring system, was announced as an unprecedented anti-inflammatory scaffold through chemistry-oriented synthesis (ChOS), a chemocentric approach. Herein, we studied how to best position the spiro[5.5]undeca ring system in kinase inhibitor space. Notably, late-stage modification of the scaffold 1 into compounds 2a-r enhanced kinase-likeness of the scaffold 1. The improvement could be depicted with (1) selectivity with target shift (from JNK-1 into GSK-3) and (2) potency (> 20-fold). In addition, ATP independent IC50 of compound 2j suggested a unique binding mode of this scaffold between ATP site and substrate site, which was explained by docking based optimal site selection and molecular dynamic simulations of the optimal binding site. Despite the shift of kinase profiling, the anti-inflammatory activity of compounds 2a-r could be retained in hyperactivated microglial cells.

Highlights

In-house 1,5-oxaza spiroquinone 1, with spiro[5.5]undeca ring system, was announced as an unprecedented anti-inflammatory scaffold through chemistry-oriented synthesis (ChOS), a chemocentric approach
In fragment based drug design, nonpolar atoms are typically used instead of polar heteroatoms to grow fragments[43]. Such a strategy cannot disrupt the potential binding of a pharmacophore to a target, so this fragment growing strategy was benchmarked to modify 1,5-oxaza spiroquinone 1
A pocket of a kinase cannot be occupied with any known inhibitor due to dissimilar shape or improper electrostatic property between the pocket and the inhibitor, NE ring systems are eligible for the pocket

Summary

Introduction

In-house 1,5-oxaza spiroquinone 1, with spiro[5.5]undeca ring system, was announced as an unprecedented anti-inflammatory scaffold through chemistry-oriented synthesis (ChOS), a chemocentric approach. The target deconvolution of scaffold 1 in kinase space showed weak inhibitory activity but suggested its potential as a selective inhibitor (Fig. 1)[10].

Results

Conclusion