Discovery of Cdc20/Hsp90 Dual-Target Inhibitors with Potent Antitumor Activity for Therapy of Acquired Resistant Melanoma.

Cell division cycle 20 homologue (Cdc20) is a cancer-promoting protein that is expressed at higher levels in tumor tissues than in neighboring tissues, and the degradation of Cdc20 is considered to be an effective strategy to inhibit tumor growth. Here, we designed Cdc20/Hsp90 dual-target inhibitors, hoping to synergistically exert antitumor effects. The preferred compound 2b exerted an extensive antitumor spectrum and lower toxicity, which closely bound to Cdc20 and Hsp90, respectively. Additionally, compound 2b exerted potent antitumor activity through reducing p53-mediated Cdc20, upregulating Bim, downregulating Cyclin B1 expression, and disturbing B-Raf and AKT pathways via destroying Hsp90 chaperone function. Furthermore, compound 2b inhibited parental melanoma growth, comparable to the marketed agent Vemurafenib and superior to the combination of Apcin and BIIB021. Interestingly, compound 2b overcame Vemurafenib-induced resistant melanoma, superior to parental melanoma, indicating that compound 2b is a promising Cdc20/Hsp90 dual-target inhibitor for therapy of acquired resistance of malignant melanoma.