Development of O’PROTACs-based degraders targeting an oncogenic viral protein

Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s Sarcoma (KS) and Primary Effusion Lymphoma (PEL), which preferentially arise in immunocompromised patients (e.g., HIV+ personnel or organ transplant recipients) and lack of effective therapeutic options. Despite the reduced incidence of KS in the era of combined Antiretroviral Therapy (cART) for HIV infection, KS still remains one of the most common AIDS-associated tumors and a leading cause of morbidity and mortality in this setting. PEL is a rapidly progressing malignancy with a median survival time of approximately 6 months, even under the combinational chemotherapy. Therefore, KSHV-induced malignancies still represent a serious threat to immunosuppressed patients due to the lack of effective therapies. This project aims to design and develop O’PROTAC-based degraders which specifically targeting LANA expression, a KSHV-encoded major oncoprotein, to interfere with the survival of KSHV+ tumor cells in vitro and in vivo. We hope we can develop new interventional strategies through targeting oncogenic virus itself for improving the outcome of these virus-associated malignancies in high-risk immunocompromised patients.