<p>Multiple myeloma (MM) ranks second only to lymphoma among hematologic malignancies in terms of incidence. Current treatment methods primarily rely on proteasome inhibitors (PIs) targeting the ubiquitin proteasome system (UPS). However, existing PIs regimens encounter several limitations, including severe adverse effects, rapidly developing resistance during treatment, and restricted therapeutic efficacy. In light of this, our work aims to explore strategies to mitigate poor conditions. We employed a systematic structural optimization process to design and synthesize the new compound BC12-3, based on prevailing PIs. JFCR39 COMPARE analysis was used to assess cytotoxic activity against 39 characteristic cancer cell lines, and the IC₅₀ value of BC12-3 was measured using CCK-8 assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry, while western blotting investigated the antitumor mechanism of BC12-3. In vivo efficacy and safety of BC12-3 and bortezomib (BTZ) were evaluated in the xenograft model. ADMET computational analyses estimated the biological safety of these two inhibitors. As a result, BC12-3 exhibited potent broad-spectrum antitumor activity in vitro particularly against MM cells; This effect was achieved by selectively inhibiting β5 subunit of proteasome activity. BC12-3 suppressed MM cell growth primarily via cell cycle arrest in G2/M phase and apoptosis induction, the related molecular pathways confirmed these phenomena. In vivo studies indicated that BC12-3 exhibits significant effect in inhibiting tumor growth, with its efficacy comparable to that of the standard therapeutic drug, BTZ. Additionally, this new compound showed an excellent safety profile. Consequently, BC12-3 holds promise as a novel therapeutic strategy for the treatment of MM.</p>