AZD1152: Repurposing for Treatment of Lupus Nephritis Driven by the Results of Clinical Trials

Background: Lupus nephritis(LN) is one of the most common and serious complications of systemic lupus erythematosus(SLE). About 20% of LN patients will progress to ESRD within 15 years. The complete remission(CR) rate of LN is not satisfactory. Combination therapy consisting of mycophenolate mofetil ,tacrolimus and glucocorticoid achieved a 20% higher CR than conventional therapy. Intrigued by its excellent clinical efficacy, we attempted to discover a new drug which is comparable to combination therapy. Methods: The Connectivity Map(CMap) database was used for drug repurposing based on the "signature" of combination therapy. And the aurora kinase B(AURKB) inhibitor, AZD1152, was predicted to have similar efficacy as combination regime. The efficacy verification was conducted with MRL/lpr mice.Transcriptome sequencing and functional experiments were performed to reveal and verify the mechanism of AZD1152, respectively. The expression and clinical significance of AURKB were evaluated with lupus-prone mice model and LN patients. Results: AZD1152 treatment significantly alleviated systemic immune activation and renal injury in MRL/lpr mice. And the efficacy of AZD1152 was comparable to combination therapy. Transcriptome profile demonstrated that AZD1152 could affect local immune-inflammatory pathway in kidney, similar to the combination regime. AURKB, the direct target of AZD1152, was upregulated and expressed in LN renal interstitial infiltrated T cells. The expression levels of AURKB was positively correlated with the activity index(AI) and serum creatinine(Scr) of LN patients. Mechanistic studies indicated that AZD1152 exerts its curative effects mainly through inhibiting AURKB-mediated T-cell proliferation. Conclusion: This is the first study to illustrate the therapeutic effect of AZD1152 in SLE and renal injury. The comparable efficacy of AZD1152 to combination regime means it is able to further reduce the side effects of drug combination. Our study also revealed the potential of AURKB as a biomarker to predict LN disease activity. In summary, our work proposed a new paradigm for drug discovery which is based on clinical trial proved therapy and approaches of drug repurposing. This strategy is able to accelerate clinical translation process as well as to build bridges between basic scientists and clinical researchers. Funding: Government Support – Non-U.S.