New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation.

Recurrent JAK2 alterations are observed in myeloproliferative neoplasms, B-cell acute lymphoblastic leukemia, and other hematologic malignancies. Currently available type I JAK2 inhibitors have limited activity in these diseases. Preclinical data support the improved efficacy of type II JAK2 inhibitors, which lock the kinase in the inactive conformation. By screening small molecule libraries, we identified a lead compound with JAK2 selectivity. We highlight analogs with on-target biochemical and cellular activity and demonstrate in vivo activity using a mouse model of polycythemia vera. We present a co-crystal structure that confirms the type II binding mode of our compounds with the "DFG-out" conformation of the JAK2 activation loop. Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance.

Investigational Janus kinase inhibitors in development for myelofibrosis.

INTRODUCTION: Since the discovery of the activating V617F mutation in Janus kinase 2 (JAK2), a number of pharmacologic inhibitors of JAK2 have entered clinical trials for patients with myelofibrosis. However, ruxolitinib, approved in 2011, remains the only one currently available for treatment of myelofibrosis, with many others having been discontinued for toxicity, and considerable uncertainty surrounding the future of those still in development. Areas covered: The available clinical data on pacritinib and momelotinib, the two agents in the most advanced phases of clinical testing in myelofibrosis, are examined in detail. NS-018 and INCB039110, selective inhibitors of JAK2 and JAK1, respectively, are also discussed. Finally, the JAK2 inhibitors no longer in clinical development are summarized in tabular form. Expert opinion: The different agents evaluated clearly differ in their kinomes, toxicity profiles and potential for myelosuppression. If approved, the JAK2-specific non-myelosuppressive inhibitor pacritinib could fulfill a major unmet need, that of patients with significant cytopenias. However, toxicity concerns persist. The data from the pivotal trials of momelotinib do not support its approval, although improvement of anemia is an important benefit. Selective JAK1 inhibition alone is unlikely to succeed in myelofibrosis. In these circumstances, rational ruxolitinib-based combinations may represent the best way forward.