UT Health San Antonio scientists have discovered novel small-molecule compounds that have allosteric signaling activity to modulate proteasome catalytic activity. The allosteric proteasome inhibitors can be used alone or in combination with existing competitive proteasome inhibitors for the treatment of cancer. Studies of combination treatment demonstrate that the allosteric inhibitors sensitize the proteasome to inhibition by established proteasome inhibitors. This synergistic effect may allow use of established proteasome inhibitors in solid cancers.
Background:
The proteasome is a proteinase complex responsible for the degradation of most intracellular proteins. Proteasome inhibitors have been shown to induce apoptosis and exhibit in vivo antitumor efficacy. Bortezomib (Velcade®) is a competitive proteasome inhibitor used to treat Multiple Myeloma and Relapsed Mantle Cell Lymphoma. However, Bortezomib has limited activity in solid tumors and inherent or acquired resistance to competitive inhibitors has been a problem.
Allosteric proteasome inhibitors represent a new class of therapeutic candidates that target the proteasome by binding outside of the active center site. Allosteric ligands generally are less likely to induce protective or adaptive actions resulting in poor response or drug resistance. The novel small-molecule compounds disrupt the functional integrity of the proteasome by interfering with long-distance structural signaling and preventing protein-protein interactions. Additionally, the compounds affect the catalytic activities of the core proteasome by allosteric interactions. In addition to allosteric inhibition of proteasome activity, studies have demonstrated that the new compounds synergistically sensitize the proteasome to inhibition by Bortezomib, thus enabling a lower dose and potentially reducing side effects and drug resistance. Additionally, solid tumor (MCF7) cells known to be resistant to Bortezomib were more sensitive to combination treatment with both compounds than with Bortezomib alone.
Commercial Applications and Advantages:
The new compounds have direct applicability to a number of oncology subspecialties and provide the following advantages over the current care:
- Novel allosteric proteasome inhibitors with activity against myeloma and solid cancer
- The proteasome is the sole target of the small-molecule compounds
- Allosteric proteasome inhibitors are less likely to induce resistance
- Novel compounds sensitize the proteasome to treatment with Bortezomib, resulting in potentially lower effective dose, fewer side effects and reduced drug resistance
- Solid tumor cells are more sensitive to combination treatment than with Bortezomib alone