Momelotinib

One of the molecular pathways that have been implicated in the pathogenesis of MF is constitutively activated and dysregulated Janus protein tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) signalling, which is believed to drive the abnormal production of pro-inflammatory cytokines in bone marrow stroma. An aberrant JAK-STAT signalling pathway in MF may or may not be caused by JAK mutations such as JAK2V617F.

Momelotinib is an adenosine triphosphate-competitive inhibitor of wild-type JAK1 and JAK2 as well as mutant JAK2V617F, which contribute to the signalling of several cytokines and growth factors that are important for hematopoiesis and immune function. Momelotinib and its major human circulating metabolite, M21, have higher inhibitory activity for JAK2 compared to other members of the JAK family - JAK3 and tyrosine kinase 2 (TYK2). Momelotinib and M21 additionally inhibit activin A receptor type 1 (ACVR1), also known as activin receptor-like kinase 2 (ALK2), which produces subsequent inhibition of liver hepcidin expression and increased iron availability, resulting in increased red blood cell production. Dysregulated JAK signalling may also contribute to inflammation and hyperactivation of ACVR1. Suppression of hepcidin by momelotinib increases circulating iron and hemoglobin, and stimulates erythropoiesis in the bone marrow.