Discovery of Highly Selective and Potent Macrocyclic JAK2 Inhibitors for the Treatment of MPNs.
Discover a potent, selective macrocyclic JAK2 inhibitor, 15au, that outperforms current MPN treatments, unlocking a promising new approach for managing this challenging disease.
This study employed macrocyclization to optimize a first-generation JAK2 inhibitor, yielding 15au - a highly selective and potent compound. 15au exhibits sub-nanomolar JAK2 inhibition with 50-80x selectivity over other JAK kinases. Mechanistic studies confirm its ability to suppress the JAK2/STAT5 pathway. 15au also demonstrates excellent pharmacokinetics and superior in vivo efficacy compared to approved MPN drugs, validating macrocyclization as an effective strategy for refining JAK2 inhibitors. These findings offer a new therapeutic approach with the potential to improve outcomes for patients with myeloproliferative neoplasms.