CS12192 Reverses Alopecia Areata by Selectively Targeting JAK3/JAK1/TBK1.

Abstract

The approval of JAK inhibitors, represented by baricitinib, for the treatment of alopecia areata (AA) has ushered in a new era. However, their excessive immunosuppressive effects have also raised numerous concerns. Therefore, the development of JAK inhibitors with different selectivities may enhance drug safety while maintaining therapeutic efficacy. CS12192, developed by our team, is a selective JAK3 inhibitor that also partially inhibits JAK1 and TBK1. In this study, we evaluate the effectiveness of CS12192 and baricitinib in a C3H/HeJ skin-transplanted AA mouse model and conduct in-depth analysis of the similarities and differences in the mechanisms of the two compounds using mass cytometry (CyTOF) and RNA-seq technology. The results show that CS12192 could reverse hair growth inhibition in AA mice in a dose-dependent manner, with the high-dose group exhibiting comparable effectiveness to baricitinib but with better safety. Further research revealed that both compounds significantly reduced the infiltration of immune cells, particularly CD8⁺ T cells, in the skin of AA animals. CyTOF and RNA-seq analysis revealed the mechanistic similarities between CS12192 and baricitinib in regulating AA-related immune cells and signaling pathways. In conclusion, CS12192, as a novel selective JAK inhibitor, holds great potential for the treatment of AA.