Development of a Janus Kinase Inhibitor Prodrug for the Treatment of Rheumatoid Arthritis

• DOI: 10.1021/acs.molpharmaceut.8b00433
• Publication Date: 2018-07-03T01:29:09Z
• Authors: Xin Wei; Jianbo Wu; Gang Zhao; Josselyn Galdamez; Subodh M. Lele; Xiaoyan Wang; Yanzhi Liu; Dhruvkumar M. Soni; P. Edward Purdue; Ted R. Mikuls; Steven R. Goldring; Dong Wang
• Keywords: Janus kinase inhibitor

While highly efficacious in treating rheumatoid arthritis (RA), the approved Janus kinase (JAK) inhibitor, Tofacitinib (Tofa, CP-690 550), has dose-dependent toxicities that limit its clinical application. In this study, we have examined whether a prodrug design targets arthritic joints would enhance Tofa's therapeutic efficacy, which may provide an opportunity for future development of safer Tofa dosing regimens. A (P-Tofa) was synthesized by conjugating drug to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer via acid cleavable carbamate linker. The efficacy single dose P-Tofa compared dose-equivalent daily oral administration adjuvant-induced (AA) rat model. Saline treated AA rats and age-matched healthy were used as controls. Observational analyses support superior sustained treatment ameliorating joint inflammation. Micro-CT histological demonstrated provided structural preservation better than Tofa. Optical imaging, immunohistochemistry, fluorescence-activated cell sorting attribute P-Tofa's passive targeting inflammatory cell-mediated sequestration. vitro culture studies reveal produced inhibition JAK/STAT6 signaling IL-4-treated murine bone marrow macrophages, consistent with gradual subcellular release Collectively, HPMA-based nanoscale potential widen window therapy RA.