Structure-Based Design of β1i or β5i Specific Inhibitors of Human Immunoproteasomes

Mammalian genomes encode seven catalytic proteasome subunits, namely, beta 1c, beta 2c, beta 5c (assembled into constitutive 20S proteasome core particles), beta 1i, beta 2i, beta 5i (incorporated into immunoproteasomes), and the thyrnoproteasome-specific subunit beta 5t. Extensive research in the past decades has yielded numerous potent proteasome inhibitors including compounds currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. Proteasome inhibitors that selectively target combinations of beta 1c/beta 1i, beta 2c/beta 2i, or beta 5c/beta 5i are available, yet ligands truly selective for a single proteasome activity are scarce. In this work we report the development of cell-permeable beta 1i and beta 5i selective inhibitors that outperform existing leads in terms of selectivity and/or potency. These compounds are the result of a rational design strategy using known inhibitors as starting points and introducing structural features according to the X-ray structures of the murine constitutive and immunoproteasome 20S core particles.