Inhibition of the proteasome has revolutionized the way hematological cancers are treated, especially multiple myeloma. As with nearly all small molecule therapeutics, resistance does occur and patients require treatment options that have a different mechanism of action. Molecules that interact with subunits of the 19S regulatory particle (19S RP) rather than the active sites in the 20S core particle (20S CP) have been shown to be effective in a variety of cancer cell types. We have recently discovered a suite of peptidomimetics with binding constants in the low micromolar range that interact with Rpn-6 by using a thermal shift assay. Rpn-6 is the main protein responsible for keeping the 19S RP and the 20S CP associated in cells to allow ubiquitin-dependent degradation to occur. These new molecules have also shown to be toxic in hematological cancers that require significant proteasome activity to survive. Studies are currently on going to determine where the peptidomimetics interact with Rpn-6 to help us rationally design better inhibitors.

Peptidomimetics that interact with Rpn-6 as new anti-cancer molecules

256th National Meeting (2018)

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