A purine scaffold HSP90 inhibitor BIIB021 has selective activity against KSHV-associated primary effusion lymphoma and blocks vFLIP K13-induced NF-κB.

[primary effusion lymphoma]

Kaposi sarcoma -associated herpes virus (KSHV )-associated primary effusion lymphomas (PEL ) have extremely poor prognosis when treated with conventional chemotherapy . KSHV-encoded viral FLICE-inhibitory protein (vFLIP ) K 13 binds to the IkappaB kinase (IKK ) complex to constitutively activate the NF-κB pathway , which has been shown to be essential for the survival and proliferation of PEL cells . The molecular chaperone HSP 90 is a component of the IKK complex and is required for its activity .We have analyzed the effect of HSP 90 inhibitors on the survival and proliferation of PEL cells and on the activity of the NF-κB pathway .We show that BIIB 021 , a purine scaffold-based orally administrable HSP 90 inhibitor , shows preferential cytotoxicity toward PEL cells as compared with non-PEL cells . The cytotoxic effect of BIIB 021 against PEL was associated with induction of cell-cycle arrest and apoptosis . BIIB 021 blocked the expression of a number of cellular proteins involved in the regulation of cell cycle and apoptosis . BIIB 021 also blocked constitutive NF-κB activity present in PEL cells , in part , by blocking the interaction of vFLIP K 13 with the IKK complex subunits . In a xenograft model of PEL , BIIB 021 significantly reduced tumor growth .BIIB 021 blocks constitutive NF-κB activity in PEL and shows preferential antitumor activity against PEL in vitro and in vivo . BIIB 021 may be a promising agent for treatment of PEL .