The global market for cancer therapeutics is over $40 billion and is anticipated to continue to rise in the future. There remains a significant unmet need for therapeutics for cancers that affect blood, bone marrow, and lymph nodes and the immune system, such as leukemia, multiple myeloma, and lymphoma. The proteasome inhibitor bortezomib, which may prevent degradation of pro-apoptotic factors permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways, has been a successful mode of treatment for such cancers. However, some patient’s cancers have been found to be resistant to the drug.

Researchers at the National Institutes of Health have developed novel hydrazone and diacyl hydrazine compounds that are inhibitors of the endoplasmic reticulum-associated protein degradation (ERAD) pathway. These compounds preferentially target the proteasome assistant ATPase p97/VCP at a site independent of nucleotide binding. The researchers have shown that these ERAD inhibitors can induce cancer cell death and can also synergize with bortezomib in cytotoxic activity. In addition to treating diseases or disorders in which inhibition of the ERAD pathway is an effective therapy, these novel compounds may also be useful in the study of protein degradation.