Discovery of Highly Selective and Potent Macrocyclic JAK2 Inhibitors for the Treatment of MPNs

The development of selective JAK2 inhibitors represents a promising therapeutic strategy for MPNs. Building upon the foundation of our first-generation JAK2 inhibitor, we employed macrocyclization-driven structural optimization to address its off-target limitations. This strategy yielded a novel class of macrocyclic JAK2 inhibitors, with compound 15au emerging as a standout candidate through systematic SAR studies. Compound 15au exhibits potent JAK2 inhibition (IC50 = 2 nM), coupled with enhanced kinase selectivity, demonstrating 89.5-, 80.5-, and 51-fold selectivity over JAK1, JAK3, and TYK2, respectively. Mechanistic studies confirm its ability to suppress the JAK2/STAT5 signaling pathway. 15au demonstrates good pharmacokinetic properties, achieving high Cmax and AUC0-t. These properties enable remarkable in vivo efficacy, where 15au outperforms both pacritinib and fedratinib in MPN models at lower doses. This work validates macrocyclization as an effective strategy for refining JAK2 inhibitors, simultaneously enhancing kinase selectivity, metabolic stability, and efficacy.