Covalent inhibitors are compounds that form a covalent link with a functional group of the target enzyme or protein. Because the reactive functional group of the inhibitors may react with different enzymes and proteins, resulting in dangerous off-target effects, they have rarely been considered as starting points in molecularly targeted drug discovery programs. However, covalent inhibitors have recently been developed as targeted covalent drugs such as afatinib, neratinib, ibrutinib, etc., by gaining selectivity for the protein. The process to form a covalent complex involves several steps. In the first step, a covalent inhibitor associates with its target protein via non-covalent interactions to form an inhibitor-protein complex, defined by the binding affinity Ki. A chemical reaction then takes place between the inhibitor and the protein to form a covalent complex, defined by the reaction rate k2. Structure-based drug design using coordinates of a complex structure of a ligand and protein is a valuable approach, which allows us to rationally design inhibitors. However, this method is not always useful for designing covalent inhibitors because an X-ray crystal structure of covalent inhibitor/protein complexes is the reaction product and does not always reflect the association state. Therefore, detailed analysis of each step is necessary in the rational design of covalent inhibitors. The naturally occurring syringolin A irreversibly inhibits proteasome by an oxa-Michael addition of the hydroxy group of the N-terminal threonine residue on the β5 subunit to the α, β-unsaturated carboxamide moiety embedded in the macrolactam. We performed a systematic structure activity relationship (SAR) study and kinetic analysis of a series of syringolin analogues consisting of macrocycles with different ring sizes. Based on the obtained information, we developed a novel potent proteasome inhibitor. Details of the synthesis and its kinetic analysis of the analogues will be presented.

Development of a covalent proteasome inhibitor and kinetic analysis of its inhibitory mechanism

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.