Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R Inhibitors

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.

Keywords: CSF1R; copper-catalyzed azide–alkyne cycloaddition; pyrrolopyrimidine; triazole.

Figure 1

Structure of the FDA-approved CSF1R inhibitors PLX-3397 and DCC-3014.

Figure 2

(A) Design concept for the triazole-based CSF1R inhibitors. (B) X-ray co-crystal structure of CSF1R (PDB 8CGC). The inhibitor is shown in green and hydrogen bonds to the protein is shown with dashed yellow lines. The structure of inhibitor III is shown with numbering system.

Scheme 1

Synthesis of 1,2,3-triazole containing pyrrolo[2,3-d]pyrimidines 18a–31b.

Figure 3

Profiling of compound 27a toward a panel of kinases at 1000 nM using ATP level equal to K_M.

Figure 4

(A) Superposition of docked 27a on CSF1R-PLX-3397 cocrystal structure 4R7H. (B) Suggested binding pose of 27a using crystal structure 4R7H.