Intrinsically disordered proteins (IDPs) involves a number of multiple regulatory and signaling events. In addition, the accumulation of IDPs results in some harmful signals happening in the pathogenesis of many human diseases.

The proteasome contains different include active complexes (such as the 26S proteasome) and a weakly active complex: the 20S proteasome. In most cells, the 20S:26S ratio is approximately 3:1.

However, when IDPs accumulate, the 26S proteasome complex will further transform into more 20S proteasome particles. As the main protease for IDPs proteolytic degradation, the 20S proteasome directly targets to IDPs.

In this article, we will precisely introduce a small molecule modulator of proteasome assembly, TCH-165.

Firstly, TCH-165 (10μM; 24 hours) treatment enhances ornithine decarboxylase (ODC) degradation, and Bortezomib (BTZ) can block this degradation. Additionally, TCH-165 enhances proteolytic degradation in a concentration-dependent manner in HEK293T cells.

Nextly, In a standard AMC-labeled peptide substrate of the proteolytic activity test. TCH-165 enhances the chymotrypsin-like (CT-L), trypsin-like (Tryp-L), and caspase-like (Casp-L) activities. the EC₅₀ values of CT-L, Tryp-L, and Casp-L are 4.2 μM,3.2 μM and 4.7 μM, respectively.

TCH-165 has the ability to enhance 20S-mediated degradation of the intrinsically disordered proteins α-synuclein (α-syn) and tau (tau441).

In the presence of various doses of TCH-165, α-syn, tau, and GADPH, and treated with purified 20S proteasome for 1h. TCH-165 improves 20S-mediated degradation of IDPs, α-syn, and tau expression. However, it does not has an effect on the degradation of structured proteins such as GAPDH.

In conclusion, TCH-165 modulates 26S assembly favoring an increase in 20S proteasome particles, resulting in an enhancement of 20S-mediated degradation of IDPs. Moreover, TCH-165 can degrade ubiquitinated substrates at effective concentrations at which enhancement of 20S proteolysis of IDP is observed. However, at high concentrations, in some specific cell types, TCH-165 may induce apoptosis in proteasome reliant cells.

TCH-165 is targeting for dysregulation of IDPs such as α-synuclein, tau (most notably associated with Alzheimer’s disease), and the proto-oncogenes ornithine decarboxylase and c-Fos.