Human Herpesvirus 8 (HHV8, also known as KSHV) is one of the commonest causes of malignancies among young adults in parts of the world and has been associated with Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). The prognosis of patients with HHV8-associated lymphoproliferative disorders is extremely poor due to their immunocompromised status and there is an urgent need for less toxic therapies for the treatment of these malignancies. We have discovered that K13, a small protein encoded by HHV8, directly interacts with the NEMO/IKK3 subunit of the IkB kinase (IKK) complex to activate the NF-kB pathway and utilizes this pathway to promote cellular survival, proliferation, transformation and cytokine secretion. The above studies have established NF-kB pathway as an important therapeutic target for the treatment of HHV8-associated malignancies. However, since NF-kB pathway plays a key role in normal immune and inflammatory response, global inhibitors of this pathway are likely to lead to severe immunosuppression, thus limiting their potential clinical utility in HHV8-infected patients. To circumvent this problem, we propose to develop a high throughput screening (HTS) assay for isolating small molecule inhibitors of K13-NEMO interaction. It is hoped that such inhibitors will specifically block K13-induced NF-kB without interfering with the physiological activation of this pathway during normal immune and inflammatory response. Furthermore, specific inhibitors of K13-NEMO interaction will serve as useful pharmacological probes to understand the various biological activities of K13.
Infection with the Human Herpesvirus 8 (HHV8) has been linked to a number of human cancers. In this project, we propose to develop a high throughput screening assay for compounds that can block the interaction of K13, a small protein encoded by HHV8, with the cellular regulatory protein NEMO. It is hoped that such compounds will not only lead to a better understanding of the biological functions of K13 but also serve as lead compounds for the development of targeted therapies for HHV8-associated malignancies.
|Tolani, B; Gopalakrishnan, R; Punj, V et al. (2014) Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. Oncogene 33:2928-37|
|Tolani, Bhairavi; Matta, Hittu; Gopalakrishnan, Ramakrishnan et al. (2014) NEMO is essential for Kaposi's sarcoma-associated herpesvirus-encoded vFLIP K13-induced gene expression and protection against death receptor-induced cell death, and its N-terminal 251 residues are sufficient for this process. J Virol 88:6345-54|
|Gopalakrishnan, Ramakrishnan; Matta, Hittu; Chaudhary, Preet M (2013) A purine scaffold HSP90 inhibitor BIIB021 has selective activity against KSHV-associated primary effusion lymphoma and blocks vFLIP K13-induced NF-?B. Clin Cancer Res 19:5016-26|
|Graham, Ciaren; Matta, Hittu; Yang, Yanqiang et al. (2013) Kaposi's sarcoma-associated herpesvirus oncoprotein K13 protects against B cell receptor-induced growth arrest and apoptosis through NF-ýýB activation. J Virol 87:2242-52|
|Yang, Yanqiang; Groshong, Jason S; Matta, Hittu et al. (2011) Constitutive NF-kappaB activation confers interleukin 6 (IL6) independence and resistance to dexamethasone and Janus kinase inhibitor INCB018424 in murine plasmacytoma cells. J Biol Chem 286:27988-97|