Small‐Molecule Inhibitors of the Proteasome's Regulatory Particle

Abstract

Cells need to synthesize and degrade proteins consistently. Maintaining a balanced level of protein in the cell requires a carefully controlled system and significant energy. Degradation of unwanted or damaged proteins into smaller peptide units can be accomplished by the proteasome. The proteasome is composed of two main subunits. The first is the core particle (20S CP), and within this core particle are three types of threonine proteases. The second is the regulatory complex (19S RP), which has a myriad of activities including recognizing proteins marked for degradation and shuttling the protein into the 20S CP to be degraded. Small‐molecule inhibitors of the 20S CP have been developed and are exceptional treatments for multiple myeloma (MM). 20S CP inhibitors disrupt the protein balance, leading to cellular stress and eventually to cell death. Unfortunately, the 20S CP inhibitors currently available have dose‐limiting off‐target effects and resistance can be acquired rapidly. Herein, we discuss small molecules that have been discovered to interact with the 19S RP subunit or with a protein closely associated with 19S RP activity. These molecules still elicit their toxicity by preventing the proteasome from degrading proteins, but do so through different mechanisms of action.

Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors

“…Targeting the 19S RP with non-peptide based small molecules is a promising approach to overcome the resistance and toxicities associated with currently licensed 20S CP inhibitors, and improve access to, and thereby activity against solid tumors. A number of small molecules have been developed as candidate inhibitors of several subunits of the 19S RP including ubiquitin receptors RPN10 and RPN13, deubiquitinases USP14, UCH37 and RPN11, and ATPase RPT4 (reviewed in [41]). USP14 has been targeted with IU1 [42] and IU1-248 [43], as well as by b-AP15 [1] and VLX-1570 [2] that also bind UCH37 [3].…”

Ubiquitin–proteasome system and the role of its inhibitors in cancer therapy

“…Moreover, KDT-11 could rather destroy the Uch3-Rpn-13 interaction or bind to a novel surface on Rpn-13. In conclusion, despite the advantage of KDT-11 over RA190, which is the selectivity of KDT-11 for Rpn-13 in MM cells, improvement of its physical properties needs more in vivo investigation [210].…”

Exploring the proteasome system: A novel concept of proteasome inhibition and regulation

“…Specific inhibition could be achieved by the development of small molecules that inhibit protein-protein interactions to interfere with the formation or stability of the super-complexes as suggested previously by Gaczynska and Osmulski (Gaczynska & Osmulski, 2015). This targeting strategy is different from the small molecule based inhibition of single 19S subunits such as ubiquitin receptors, DUB or ATPases (Muli, Tian, & Trader, 2019). These compounds influence protein degradation by inhibiting for example binding of ubiquitinated proteins to the respective 19S receptors RPN10 and RPN13, impeding activity of deubiquitinases such as USP14, UCH37 and RPN11, or blocking ATPase activity of the 19S base subunits (as recently summarized by (Muli et al, 2019)).…”

“…This targeting strategy is different from the small molecule based inhibition of single 19S subunits such as ubiquitin receptors, DUB or ATPases (Muli, Tian, & Trader, 2019). These compounds influence protein degradation by inhibiting for example binding of ubiquitinated proteins to the respective 19S receptors RPN10 and RPN13, impeding activity of deubiquitinases such as USP14, UCH37 and RPN11, or blocking ATPase activity of the 19S base subunits (as recently summarized by (Muli et al, 2019)).…”