Discovery of New Quinazolinone and Benzimidazole Analogs as Tubulin Polymerization Inhibitors with Potent Anticancer
Boye Jiang1,2, Juan Zhang3, Kai Shao1
1Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Abstract:
Background/Objectives: Cancer persists as a leading concern in the current medical field, and current therapies are limited by toxicity, cost, and resistance. Targeted inhibition of tubulin polymerization is considered as a promising therapeutic strategy for cancer treatment. Methods: Thirty-one new tubulin polymerization inhibitors were designed via molecular hybridization techniques, and BLI technology was employed to quantitatively investigate their interactions with tubulin. Antiproliferative activities against MCF-7, MDA-MB-231, A549, and HeLa cell lines was evaluated using the CCK8 assay. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. The anti-tumor activity of compound B6 was validated in a mouse melanoma tumor model. Results: Compounds exhibited varying degrees of antiproliferative activity against four tumor cell lines. Among them, compound B6 was the most promising candidate and displayed strong broad-spectrum anticancer activity with an average IC50 value of 2 μM. The mechanism studies revealed that compound B6 inhibited tubulin polymerization in vitro, disrupted cell microtubule networks, and arrested the cell cycle at G2/M phase. Furthermore, B6 displayed significant in vivo antitumor efficacy in a melanoma tumor model with tumor growth inhibition rates of 70.21% (50 mg/kg). Conclusions: This work shows that B6 is a promising lead compound deserving further investigation as a potential anticancer agent.
Insights
A novel compound, B6, effectively inhibits cancer cell growth by targeting tubulin polymerization. This promising anticancer agent demonstrated significant tumor reduction in preclinical models, warranting further development.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Cancer remains a significant global health challenge with limitations in current treatments.
- Targeting tubulin polymerization presents a promising strategy for developing novel anticancer therapies.
Purpose of the Study:
- To design and synthesize novel tubulin polymerization inhibitors.
- To evaluate the anticancer potential of these compounds, focusing on compound B6.
Main Methods:
- Molecular hybridization for inhibitor design.
- Biolayer interferometry (BLI) for tubulin interaction analysis.
- Cell-based assays (CCK8, flow cytometry) for antiproliferative and mechanistic studies.
- In vivo efficacy assessment in a melanoma mouse model.
Main Results:
- Compound B6 exhibited potent broad-spectrum antiproliferative activity (average IC50 of 2 μM).
- B6 inhibited tubulin polymerization, disrupted microtubule networks, and induced G2/M cell cycle arrest.
- Significant in vivo antitumor efficacy was observed, with 70.21% tumor growth inhibition at 50 mg/kg.
Conclusions:
- Compound B6 is a highly promising lead candidate for anticancer drug development.
- Further investigation into B6 as a potential therapeutic agent is warranted.
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