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Antitumor effect of BC12-3 on multiple myeloma via proteasome inhibition
Huiying Li1, Geng Jia2, Naixin Zhang1
1Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China.
Abstract:
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.
Insights
A new proteasome inhibitor, BC12-3, shows potent anti-multiple myeloma (MM) activity by selectively inhibiting proteasome activity. This compound effectively suppresses tumor growth and induces apoptosis, offering a promising new therapeutic strategy for MM treatment.
Area of Science:
- Hematologic Malignancies
- Drug Discovery
- Cancer Therapeutics
Background:
- Multiple myeloma (MM) is a significant hematologic malignancy with current treatments facing limitations like resistance and adverse effects.
- Existing proteasome inhibitors (PIs) targeting the ubiquitin proteasome system (UPS) have shown efficacy but require improvement.
- There is a critical need for novel therapeutic strategies with enhanced efficacy and safety profiles for MM.
Purpose of the Study:
- To design and synthesize a novel compound, BC12-3, with improved therapeutic potential for multiple myeloma.
- To evaluate the in vitro and in vivo antitumor activity and safety of BC12-3.
- To elucidate the mechanism of action of BC12-3 in multiple myeloma cells.
Main Methods:
- Systematic structural optimization was used to design and synthesize BC12-3 based on existing PIs.
- Cytotoxic activity was assessed using JFCR39 COMPARE analysis and CCK-8 assays.
- Cell cycle distribution, apoptosis, and molecular pathways were analyzed by flow cytometry and western blotting.
- In vivo efficacy and safety were evaluated in a xenograft model, with ADMET analyses for safety estimation.
Main Results:
- BC12-3 demonstrated potent broad-spectrum antitumor activity in vitro, particularly against MM cells, by selectively inhibiting the proteasome β5 subunit.
- The compound induced G2/M cell cycle arrest and apoptosis in MM cells, with confirmed molecular pathway involvement.
- In vivo studies showed BC12-3 significantly inhibited tumor growth, with efficacy comparable to bortezomib (BTZ), and exhibited an excellent safety profile.
Conclusions:
- BC12-3 is a novel proteasome inhibitor with significant in vitro and in vivo efficacy against multiple myeloma.
- The compound's mechanism involves selective proteasome inhibition, leading to cell cycle arrest and apoptosis.
- BC12-3 presents a promising new therapeutic candidate for the treatment of multiple myeloma, offering a favorable safety profile.
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