Abstract: The invention provides therapeutic and prophylactic compounds and methods for altering the activity of pyruvate dehydrogenase kinase (e.g. PDK1, PDK2, PDK3, PDK4). Such therapies are useful for the treatment of neoplasia. The invention further provides therapeutic and prophylactic compounds and methods of altering pyruvate dehydrogenase activity to treat or prevent cell death related to ischemia.

Abstract: The present invention discloses that OS-9 interacts with both HIF-1a and HIF-1a prolyl hydroxylases. Overexpression of OS-9 promotes the hydroxylation of HIF-1a, HIF-1a binding to VHL, proteasomal degradation of HIF-1a, and loss of HIF-1-mediated transcription. OS-9 loss-of-function increases HIF-1a protein levels and HIF-1-mediated transcription under non-hypoxic conditions. These data indicate that OS-9 is an essential component of a multiprotein complex that regulates HIF-1a protein levels in an O2 dependent manner. Agents which modulate this complex, and methods to identify such agents, are disclosed.