# Revisiting Janus kinases as molecular drug targets for rheumatic diseases

## TL;DR

This review explores JAKs as drug targets for rheumatic diseases and suggests strategies for developing better inhibitors.

## Contribution

The paper proposes new strategies for designing next-generation JAK inhibitors based on structural analysis.

## Key findings

- Structural data on JAKs reveal opportunities for selective inhibitors.
- Current JAK inhibitors for rheumatoid arthritis are summarized.
- Binding modes of inhibitors are analyzed to guide future drug design.

## Abstract

Janus kinase (JAK) family members, as upstream regulators, phosphorylate not only themselves but also cytokine receptors and signal transducer and activator of transcription (STAT) proteins in the JAK-STAT signaling pathway. The JAK-STAT pathway is associated with various cellular processes, such as cell proliferation, cell death, and immune responses. Considering that the JAK-STAT pathway is involved in immunity, dysfunctional JAKs can cause autoimmune diseases, including rheumatoid arthritis. Therefore, several inhibitors have been developed to inhibit the function of JAKs in the case of abnormal JAK-STAT signaling. Emerging structural data on JAKs highlight the opportunities to design selective inhibitors that can overcome mutation-driven resistance. Therefore, novel JAK inhibitors need to be developed. In this review, we discuss the principal structural features of JAKs, focusing on the active site. In addition, we summarized the updated JAK inhibitors indicated for rheumatoid arthritis that are available in the pharmaceutical market. The binding modes of JAK inhibitors have also been described. Based on the structural analysis of JAKs and their inhibitors, we propose strategies for developing next-generation JAK inhibitors.