PSMD2 inhibitor

PSMD2 inhibitors are a class of therapeutic agents designed to target the PSMD2 (also known as Rpn1) subunit of the 19S regulatory particle within the 26S proteasome. PSMD2 serves as a critical ubiquitin receptor that recognizes and binds polyubiquitinated protein substrates, facilitating their entry into the 20S catalytic core for degradation. In multiple myeloma (MM), PSMD2 is frequently overexpressed and associated with poor prognosis and resistance to standard proteasome inhibitors (PIs) like bortezomib. Research indicates that inhibiting PSMD2 disrupts proteasome function independently of the 20S core, leading to the accumulation of ubiquitinated proteins, activation of the unfolded protein response (UPR), and induction of endoplasmic reticulum (ER) stress. Furthermore, PSMD2 inhibition triggers DNA damage and activates the cGAS–STING–TBK1 signaling pathway, resulting in type I interferon production and immunogenic cell death (ICD). This dual mechanism of action makes PSMD2 an attractive target for overcoming PI resistance in hematologic malignancies.

Other names

Rpn1 inhibitorRpn-1 inhibitorRpn 1 inhibitorPSMD2/Rpn1 inhibitor