Unveiling Benzoxazole-Substituted Thiazolyl-Pyrazole Derivatives Inducing Apoptosis by Targeting β-Tubulin and Caspase-3
Burak Kuzu1, Mustafa Cakir2, Eda Acikgoz3
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Van Yuzuncu Yil University, Van, 65080, Türkiye.
Abstract:
In the present study, the biological activities of novel compounds (BP-1 to BP-6), designed as antitubulin agents, were systematically evaluated, with a particular focus on their effects on the triple-negative breast cancer cell line MDA-MB-231 and non-cancerous cell line MCF-10A. BP-2 and BP-6 demonstrated micromolar-range antiproliferative activity against MDA-MB-231 cancer cells, with IC5 0 values of 8 and 4 µM, respectively, comparable to nocodazole (3 µM), and showed selective cytotoxicity over normal MCF-10A cells, with selectivity indices of approximately 3.3 and 8. In vitro analyses revealed that BP-2 and more notably BP-6 significantly inhibited cell proliferation in a time- and dose-dependent manner, disrupted microtubule organization through the downregulation of β-tubulin expression, and induced apoptosis, as evidenced by increased levels of Cleaved Caspase-3 and distinct apoptotic morphological changes. Among the tested compounds, BP-6 exhibited the most potent antiproliferative and proapoptotic activity, with an IC5 0 value close to that of NOC. Molecular docking supported these findings by showing strong binding affinities of BP-6 to both β-tubulin and Caspase-3, indicating a dual-targeted mechanism. Furthermore, molecular dynamics simulations confirmed the stable binding and dynamic integrity of BP-6 within both β-Tubulin and Caspase-3 targets, underscoring its potential as a robust candidate for anticancer drug development.
Insights
Novel compounds BP-2 and BP-6 show potent anticancer activity against triple-negative breast cancer cells by inhibiting proliferation and inducing apoptosis. BP-6 demonstrates significant potential as a dual-targeted anticancer drug candidate.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) remains a challenging subtype with limited targeted therapies.
- Antitubulin agents are a validated class of anticancer drugs, but resistance and toxicity are concerns.
- Developing novel agents with improved efficacy and selectivity is crucial for TNBC treatment.
Purpose of the Study:
- To evaluate the biological activities of novel antitubulin compounds (BP-1 to BP-6).
- To assess the efficacy and selectivity of these compounds against the MDA-MB-231 TNBC cell line and the non-cancerous MCF-10A cell line.
- To elucidate the mechanism of action of the most promising compounds.
Main Methods:
- In vitro antiproliferative assays using MDA-MB-231 and MCF-10A cell lines.
- Western blotting to assess β-tubulin expression and Cleaved Caspase-3 levels.
- Morphological analysis for apoptosis detection.
- Molecular docking and molecular dynamics simulations for target binding assessment.
Main Results:
- Compounds BP-2 and BP-6 exhibited significant antiproliferative activity against MDA-MB-231 cells (IC50 values of 8 µM and 4 µM, respectively).
- BP-6 showed potent and selective cytotoxicity against cancer cells over normal cells (selectivity index ~8).
- BP-6 demonstrated dose- and time-dependent inhibition of cell proliferation, disrupted microtubule organization via β-tubulin downregulation, and induced apoptosis.
- Molecular docking and simulations confirmed stable binding of BP-6 to β-tubulin and Caspase-3, suggesting a dual-targeted mechanism.
Conclusions:
- BP-6 is a highly promising antitubulin agent with potent antiproliferative and proapoptotic activities against TNBC.
- The dual-targeting mechanism involving β-tubulin and Caspase-3 contributes to BP-6's efficacy.
- BP-6 warrants further investigation as a potential therapeutic candidate for triple-negative breast cancer.
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
01:15Drugs that Stabilize Microtubules
01:10Drugs that Destabilize Microtubules
01:24Caspases
01:30Apoptosis