TCH-165

TCH-165 is a modulator of proteasome assembly.¹ It selectively activates the chymotrypsin-like, trypsin-like, and caspase-like activities of the 20S proteasome (EC₅₀s = 4.2, 3.2, and 4.7 µM, respectively) over the same activities of the 26S proteasome (EC₅₀s = >70 µM for all) but also inhibits the chymotrypsin-like activity of the 20S proteasome (IC₅₀ = 1.44 µM) in cell-free assays.^1,2 TCH-165 (10 µM) increases the 20S proteasome-dependent degradation of the intrinsically disordered proteins α-synuclein and tau.¹ It enhances disassembly of the 26S proteasome with a concomitant increase in 20S proteasome levels in HEK293T cells in a time-and concentration-dependent manner. TCH-165 (100 mg/kg, p.o.) decreases tumor volume in an RPMI-8226 multiple myeloma mouse xenograft model.³ It decreases infarct volume as a percentage of the area at risk in a mouse model of cardiac ischemia-reperfusion injury induced by left anterior descending coronary artery occlusion when administered at a dose of 50 mg/kg.⁴

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1. Njomen, E., Osmulski, P.A., Jones, C.L., et al. Small molecule modulation of proteasome assembly. Biochemistry 57(28), 4214-4224 (2018).

2. Azevedo, L.M., Lansdell, T.A., Ludwig, J.R., et al. Inhibition of the human proteasome by imidazoline scaffolds. J. Med. Chem. 56(14), 5974-5978 (2013).

3. Njomen, E., Vanecek, A., Lansdell, T.A., et al. Small molecule 20S proteasome enhancer regulates MYC protein stability and exhibits antitumor activity in multiple myeloma. Biomedicines 10(5), 938 (2022).

4. Gao, J., Su, H.-X., Li, P.-B., et al. TCH-165 attenuates cardiac ischaemia/reperfusion injury by balancing mitochondrial dynamics via increasing proteasome activity. Eur. J. Pharmacol. 957, 176011 (2023).