Dual-target Janus kinase (JAK) inhibitors: Comprehensive review on the JAK-based strategies for treating solid or hematological malignancies and immune-related diseases

Abstract

Janus kinases (JAKs) are the non-receptor tyrosine kinases covering JAK1, JAK2, JAK3, and TYK2 which regulate signal transductions of hematopoietic cytokines and growth factors to play essential roles in cell growth, survival, and development. Dysregulated JAK activity leading to a constitutively activated signal transducers and activators of transcription (STAT) is strongly associated with immune-related diseases and cancers. Targeting JAK to interfere the signaling of JAK/STAT pathway has achieved quite success in the treatment of these diseases. However, inadequate clinical response and serious adverse events come along by the treatment of monotherapy of JAK inhibitors. With better and deeper understanding of JAK/STAT pathway in the pathogenesis of diseases, researchers start to show huge interest in combining inhibition of JAK and other oncogenic targets to realize a broader regulation on pathological processes to block disease development and progression, which has hastened extensive research of dual JAK inhibitors over the past decades. Until now, studies of dual JAK inhibitors have added BTK, SYK, FLT3, HDAC, Src, and Aurora kinases to the overall inhibitory profile and demonstrated significant advantage and superiority over single-target inhibitors. In this review, we elucidated the possible mechanism of synergic effects caused by dual JAK inhibitors and briefly describe the development of these agents.