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Background:  The inactivation of tumor-suppressor p53 plays an important role in second generation anti-androgens (SGAs) drug resistance and neuroendocrine differentiation in castration-resistant prostate cancer (CRPC). The reactivation of p53 by blocking the MDM2–p53 interaction represents an attractive therapeutic remedy in cancers with wild-type or functional p53. Whether MDM2-p53 inhibitor could overcome SGAs drug resistance in CRPC is still needed further research. Here, we investigated the anti-tumor efficacy and mechanisms of a novel MDM2-p53 inhibitor XR-2 in CRPC.   Methods:  To investigate the functions and mechanisms of XR-2 in prostate cancer,  in vitro  and  in vivo  biofunctional assays were performed. Western blot and qRT-PCR assay were performed to detect the protein and mRNA expression levels of indicated genes. CCK8, colony formation, flow cytometry and senescence assays were performed for cell function identifications. RNA-sequencing and bioinformatics analysis were mainly used to identify the influence of XR-2 on prostate cancer cells transcriptome. Subcutaneous 22Rv1 derived xenografts mice model was used to investigate the  in vivo  anti-tumor activity of XR-2. In addition, the broad-spectrum anti-tumor activities  in vivo  of XR-2 were evaluated by different xenografts mice models.   Results:  XR-2 could directly bind to MDM2, potently reactivate the p53 pathway and thus induce cell cycle arrest and apoptosis in wild-type p53 CRPC cell lines. XR-2 also suppresses the AR pathway as p53 regulates AR transcription inhibition and MDM2 participates in AR degradation. As a result, XR-2 efficiently inhibited CRPC cell viability, showed a synergistic effect with enzalutamide and overcame enzalutamide resistance both  in vitro  and  in vivo . Moreover, results illustrated that XR-2 possesses broad-spectrum anti-tumor activities  in vivo  with favourable safety.   Conclusion:  MDM2-p53 inhibitor (XR-2) possesses potently prostate cancer progresses inhibition activity both  in vitro  and  in vivo . XR-2 shows a synergistic effect with enzalutamide and overcomes enzalutamide resistance.

Novel MDM2 Inhibitor XR-2 Exerts Potent Anti-Tumor Efficacy and Overcomes Enzalutamide Resistance in Prostate Cancer