# Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R Inhibitors

## TL;DR

This study explores new triazole-substituted pyrrolopyrimidines as effective and selective inhibitors of the CSF1R protein.

## Contribution

The paper introduces a new series of triazole analogues with high CSF1R inhibition and unique binding characteristics.

## Key findings

- 27 out of 28 synthesized compounds showed better CSF1R inhibition than the reference drug PLX-3397.
- Compound 27a exhibited high selectivity for CSF1R but also inhibited ABL, SRC, and YES kinases.
- Molecular docking revealed two distinct binding poses of 27a in CSF1R structures.

## Abstract

6-Aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines have promising properties as colony-stimulating factor 1 receptor (CSF1R) inhibitors. Inspired by these antagonists, two series of 1,2,3-triazole analogues (28 compounds) were synthesized and evaluated as CSF1R inhibitors. Enzymatic IC50 profiling showed that 27 of the 28 derivatives had lower IC50 than the reference drug PLX-3397. Three derivatives displayed CSF1R Ba/F3 cellular IC50 well below 1 µM. Profiling of the most promising triazole analogue (compound 27a) toward a panel of kinases reveals a high selectivity for CSF1R with respect to its family kinases, but 27a also inhibits ABL, SRC, and YES kinases. Molecular docking of 27a toward two CSF1R X-ray structures identified two different ligand-inverted binding poses, which triggers interest for further investigations.