23 November 2018

A newly developed drug is showing promise in the laboratory for the treatment of multiple myeloma, researchers have reported.

Scientists at the Medical University of South Carolina, USA, screened 20,000 compounds to identify treatments which could re-sensitise multiple myeloma cells to proteasome inhibitors such as bortezomib.

Dr Nathan Dolloff and colleagues explain that new therapies are urgently needed for refractory patients and those who develop resistance to the standard-of-care drugs.

The team identified one, E61, which was particularly able to reverse resistance to proteasome inhibitors. Investigating E61 further, they found that the primary molecular targets of this compound are members of the protein disulfide isomerase family.

Treatment with E61 on its own and in combination with bortezomib increased cell death in multiple myeloma cells in the lab, and also improved survival in mouse models.

In an article published last week in the journal Leukemia, the researchers state that E61 "enhanced the activity of bortezomib without any adverse effects". Further work to improve E61 led to the development of E64FC26, a new lead compound which was shown to be even more effective than E61.

They write: "This work demonstrates the potential of E64FC26 as an early drug candidate and the strategy of targeting multiple protein disulfide isomerase isoforms for the treatment of refractory multiple myeloma and beyond."

Dr Dolloff concludes: "Protein disulfide isomerase is an attractive target in oncology, but good protein disulfide isomerase inhibitors have been hard to find. The compounds we discovered have a lot of advantages, including high potency and good drug-like properties.

"We hope that those strengths translate into an effective new drug that can ultimately help patients."

Source: Robinson, R.M., Reyes, L., Duncan, R.M., Bian, H., Reitz, A.B., Manevich, Y., McClure, J.J., Champion, M.M., Chou, C.J., Sharik, M.E., Chesi, M., Bergsagel, P.L., Dolloff, N.G. (2018) “Inhibitors of the protein disulfide isomerase family for the treatment of multiple myeloma”, Leukemia, available at doi: 10.1038/s41375-018-0263-1


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