Momelotinib's unique polypharmacology supports indication expansion beyond myelofibrosis

Abstract Momelotinib (Ojjaara / Omjjara), a clinically differentiated JAK inhibitor, not only addresses symptoms and splenomegaly associated with myelofibrosis (MF) through JAK1/JAK2 inhibition but also targets activin A receptor type 1 (ACVR1) to improve anemia. While other JAK inhibitors primarily address symptoms and splenomegaly, momelotinib also targets the underlying cause of anemia, a significant complication in MF, and reduces the need for blood transfusions. The experiments described herein further characterize momelotinib's kinome selectivity profile and establish rationale for disease expansion beyond myelofibrosis. Cellular, biochemical, and proteome-wide chemoproteomic assays were conducted to identify and confirm kinase targets of momelotinib and other JAK inhibitors approved for MF. These studies revealed that momelotinib has a distinctive kinase selectivity profile that, in addition to the ACVR1/ALK2 kinase, also targets the rho-associated kinases (ROCK1 and ROCK2), Inhibitor of kappa B kinase complex (IKK), and interleukin-1 receptor-associated kinase 1 (IRAK1). Furthermore, cellular reporter assays demonstrated that momelotinib inhibited NF-kB activity stimulated by pro-inflammatory cytokines, including canonical (TNFα, IL-1β) and non-canonical (RANKL, LIGHT) activators. These findings confirm momelotinib's unique polypharmacology and therapeutic potential in pro-inflammatory diseases beyond MF, namely Vacuoles E1 X-chromosome Autoinflammatory Somatic syndrome (VEXAS), lower-risk myelodysplastic syndrome (LR-MDS), and graft-versus-host disease (GvHD) where these pathways are significantly impaired and there continues to be a high medical need.