4qls

Publication Abstract from PubMed

Mammalian genomes encode seven catalytic proteasome subunits, namely, beta1c, beta2c, beta5c (assembled into constitutive 20S proteasome core particles), beta1i, beta2i, beta5i (incorporated into immunoproteasomes), and the thymoproteasome-specific subunit beta5t. 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 beta1c/beta1i, beta2c/beta2i, or beta5c/beta5i are available, yet ligands truly selective for a single proteasome activity are scarce. In this work we report the development of cell-permeable beta1i and beta5i 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.

Structure-Based Design of beta1i or beta5i Specific Inhibitors of Human Immunoproteasomes.,de Bruin G, Huber EM, Xin BT, van Rooden EJ, Al-Ayed K, Kim KB, Kisselev AF, Driessen C, van der Stelt M, van der Marel GA, Groll M, Overkleeft HS J Med Chem. 2014 Jul 15. PMID:25006746^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.