Engineering SIM-1 and MZ-1 PROTACs for enhanced target degradation in KSHV-infected immortalized endothelial cells

Abstract

Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s Sarcoma (KS), which are still lacking of treatment options. Members of the bromodomain and extra-terminal domain (BET) family, especially bromodomain-containing protein 4 (BRD4), play important roles in RNA polymerase II–mediated transcriptional regulation and are required for the expression of many tumor-driving oncogenes in various cancer cells. Therefore, BET proteins have become attractive targets for anticancer drug development. Our recent studies showed that KSHV-infected immortalized endothelial cells displayed strong resistance to BET inhibitors such as (+)-JQ1. In contrast, we found out MZ-1 and SIM-1, two of BRD4 PROTAC degraders, as effective inhibitors of cell growth in these cells. To develop PROTAC molecules with enhanced BRD4 degradation potency, we introduced an ( S )-methyl group at the benzylic position of the VHL ligand in the VHL-based BRD4 PROTACs MZ-1 and SIM-1, thereby designing and generating MZ-1-ME and SIM-1-ME, respectively. In KS cellular model, MZ-1-ME and SIM-1-ME exhibited enhanced BRD4 degradation and anticancer activities compared with their parental compounds, which may represent promising PROTACs for development of BRD4-targeted therapies against KS.