Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders driven in large part by aberrant activation of the Janus kinase‐signal transducer and activator of transcription (JAK‐STAT) signaling pathway via the JAK2 V617F and related mutations. The success of first‐generation ATP competitive JAK2 inhibitors has validated JAK2 as a therapeutic target, yet clinical benefits remain constrained by issues of off target toxicity, limited mutation allele burden reduction, and the emergence of persistence or resistance. In this review, we focus on a rapidly emerging design paradigm: targeting novel binding sites on JAK2 beyond the canonical ATP pocket—including allosteric sites, covalent anchor residues, and pseudokinase regulatory domains. We summarize structural and computational insights into these new sites, compare mechanistic and therapeutic advantages (such as enhanced selectivity, reduced cross JAK inhibition and potential to overcome resistance) and evaluate preclinical and early clinical evidence. We further identify remaining challenges in the development of next generation JAK2 inhibitors—such as site validation, ligand residence time, covalent binding safety, and rational combination therapies—and propose future directions for translation into the MPN clinic. By refocusing the JAK2 inhibitor field around novel binding site exploitation, we suggest a path toward more potent, selective and enduring therapies for MPN patients.
Zhao et al. (Fri,) studied this question.