# New Quinoline Kinase Inhibitors With Good Selectivity for NAK Kinases and Anti‐Tumor Activity Against Ewing Sarcoma

## TL;DR

New quinoline compounds were developed that selectively inhibit NAK kinases and show anti-tumor activity against Ewing Sarcoma, a type of childhood cancer.

## Contribution

The discovery of new quinoline kinase inhibitors with selectivity for NAK kinases and anti-tumor activity against Ewing Sarcoma.

## Key findings

- Quinoline derivatives showed anti-proliferative activity against Ewing Sarcoma.
- The compounds selectively inhibited the NAK family of kinases, particularly GAK, at nanomolar levels.
- Enzyme kinetic assays confirmed the selectivity and inhibition of GAK by these quinoline derivatives.

## Abstract

In the past few years, several novel anticancer agents targeting protein kinases have been discovered expanding the available therapeutic arsenal. However, few new therapeutic approaches have been developed for the treatment of childhood cancer. To this end, we have been making efforts to contribute to this important field. Herein, we identified a series of new 4,6‐disubstituted quinoline derivatives from our in‐house quinoline chemical library that showed promising anti‐proliferative activity against Ewing Sarcoma (ES). This interesting observation engaged us to further investigate these derivatives since this type of cancer is among the most common bone cancers in children. Evaluation of the quinoline derivatives against a panel of kinases demonstrated generally narrow selectivity profiles of this compound class. Interestingly, the main kinases that were inhibited belonged to the NAK family of kinases, in particular, the family member cyclin G‐associated kinase (GAK) which was inhibited at nanomolar range in enzyme kinetic assays.

Focusing on the discovery of new therapeutics for childhood cancer, novel quinoline derivatives were synthesized and demonstrated activity against Ewing sarcoma. A target search was performed against a panel of kinases, and the compounds showed selectivity for the NAK family, mainly GAK, which was confirmed by enzyme kinetic assays.