Discovery of a highly selective JAK2 inhibitor with a furopyrimidine scaffold

Janus kinases (JAKs) mediate cytokine and growth factor signaling by phosphorylating STAT proteins, playing a critical role in immune regulation. Among JAK family, JAK2 drives hematopoietic and immune signaling. Its dysregulation promotes myeloproliferative neoplasms (MPN) by impairing hematopoietic stem cell function. Selective JAK2 inhibition offers a promising therapeutic strategy for effective and safe MPN treatment. Starting from a non-selective JAK inhibitor, we synthesized a series of furopyrimidine derivatives to discover potent, JAK2-selective inhibitors. Structural optimization led to potent JAK2 inhibitors with improved selectivity. Further refinements led to compound 14 , which exhibited approximately 10-fold selectivity for JAK2 over JAK1 and negligible inhibition of JAK3 and TYK2 in biochemical assays. These findings provide a framework for designing novel JAK2-selective inhibitors with improved potency and specificity for MPN therapy. • A novel series of furopyrimindine derivatives has been discovered as JAK inhibitors • Compound 14 exhibited high selectivity toward JAK2 among the JAK family. • Docking study suggested that terminal heteroatoms on substituents enhance selectivity.