Since discovered in last century, the proteasome has become an exciting research field for developing drugs that inhibit the protease subunits to halt proteasomal function, which can lead to apoptosis. However, resistance has been observed with those inhibitors which makes developing new molecules targeting different subunits on proteasome an urgent task. A considerable number of subunits in proteasome processes no protein degradation function yet they are crucial for proteasome stability. One example is Rpn-6, it is required to associate the regulatory particle with the core particle to form the full 26S proteasome. We have discovered a peptoid molecule named TXS-8 that possesses moderate binding affinity towards Rpn-6 <i>in vitro</i> and it has toxicity towards some hematological cancer cell lines. Our further experimental data suggests that the cell death caused by dosing TXS-8 is unrelated to proteasome malfunction or deteriorated structural integrity so we suspect that Rpn-6 may serve more than being a subunit of the proteasome. Moreover, we discovered that TXS-8 is selective towards Rpn-6 through a pull-down assay which makes TXS-8 a promising molecule for further research. Future work includes studies to determine what other role Rpn-6 plays in hematological cancers.

Discovery of small molecules that interact with Rpn-6 and are toxic to hematological cancers

2019 Fall National Meeting

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