Compound 16 interaction with 20s B5 sub-unit

3D Model

The 26s proteasome is involved in intracellular degradation within multiple pathways including signalling, apoptosis, and inflammatory responses. While there are avariety of synthetic and natural inhibitors that will bind to the beta 5 sub-unit (which have chymotrypsin-like mechanisms); their ‘warhead’ structures lack specificity, are often reactive, and are unstable. Compound 16, shown here non-covalently interacting with the B5 subunit of a beta ring, is a novel compound developed through sequential optimisation of S-homo-phenylalanine which targets the chymotrypsin-like mechanisms. Compound 16 forms a near-optimal interaction at the S3 binding pocket with a neopentyl asparagine alongside weaker S1 binding pocket and sub-pocket interactions. This compound has higher affinity to B5 (Ki=1.2nM) in comparison to the covalent inhibitor Bortezomib (Ki=0.56nM). By solely inhibiting the B5 subunit it is capable of inhibiting cell cancer proliferation. Blackburn et al, 2010. Doi: doi:10.1042/BJ20100383