Advances in the design and discovery of next-generation janus kinase-2 (JAK2) inhibitors for the treatment of myeloproliferative neoplasms.

Introduction: Myeloproliferative neoplasms (MPNs) are rare hematopoietic disorders driven by mutations in the JAK-STAT signaling pathway genes. While JAK2 inhibitors have transformed MPN treatment, they do not eliminate the malignant clone or prevent disease progression in most patients. This limitation underscores the need for more effective therapies.

Area covered: This review examines the evolution of JAK2 inhibitors for treating MPNs. Current JAK2 inhibitors primarily function as type I inhibitors, targeting the active kinase conformation, but their effectiveness is limited by ongoing JAK-STAT signaling. To overcome these limitations, next-generation therapies, such as type II JAK2 inhibitors and pseudokinase domain inhibitors, are being developed to target inactive kinase conformations and alternative signaling pathways. Furthermore, combination therapies with PI3K, mTOR, CDK4/6 inhibitors, and epigenetic modulators are being investigated for their potential synergistic effects, aiming for deeper and more durable responses in MPN patients.

Expert opinion: Next-generation JAK2 inhibitors are needed to enhance current MPNs treatments by overcoming resistance, improving selectivity, targeting specific patient groups, and exploring combination therapies. Addressing challenges in drug design, preclinical testing, and clinical trials is crucial. Developing dual or multiple inhibitors targeting JAK2 and other MPN-related pathways is urgent to address complex signaling networks and improve efficacy.