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Updated: Feb 2, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Rational design of novel procaspase-3 activators for the targeted therapy of triple-negative breast cancer
Zhongyuan Guo1, Huan Liu2, Chenxiaoning Meng3
1College of Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China; Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Abstract:
Triple-negative breast cancer (TNBC) remains a formidable clinical challenge owing to its aggressive phenotype and limited treatment options. To address this, we employed ligand-based rational drug design coupled with scaffold hybridization to develop a series of novel procaspase-3 activators. From 28 designed compounds, F17 and F21 emerged as lead candidates, exhibiting superior in vitro procaspase-3 activation. Density functional theory calculations confirmed their enhanced zinc-binding affinity, with adsorption energies (Eads) of -14.8332 eV (F17) and -14.8797 eV (F21), compared to -12.7474 eV for PAC-1, along with stronger electrostatic potential minima (-67.20 and -66.99 kcal/mol, respectively). In silico ADMET profiling indicated favorable drug-like properties, including good aqueous solubility, low blood-brain barrier penetration, and moderate intestinal absorption. In TNBC MDA-MB-231 models, both compounds demonstrated potent anti-proliferative activity, with IC50 values of 25.82 μM (F17) and 25.03 μM (F21) after 48 h, outperforming PAC-1 (33.81 μM). They also significantly inhibited cell migration, reducing wound closure to 11.19% (F21) compared with 20.60% in controls, and induced caspase-3-dependent apoptosis. Importantly, in vivo neurotoxicity assessments revealed no significant neuronal damage at doses up to 50 mg/kg, underscoring their improved safety profile over earlier activators. These results establish F21 as a particularly promising preclinical candidate and provide a rational framework for developing target-specific, neurotoxicity-sparing procaspase-3 activators for TNBC therapy.
Insights
New procaspase-3 activators, F17 and F21, show potent anti-cancer effects against triple-negative breast cancer (TNBC) with reduced neurotoxicity. These novel compounds offer a promising therapeutic strategy for TNBC treatment.
Area of Science:
- Medicinal Chemistry
- Oncology
- Computational Chemistry
Background:
- Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to its aggressive nature and limited treatment options.
- Procaspase-3 activators are an emerging class of anti-cancer agents, but their clinical utility has been hampered by potential neurotoxicity.
Purpose of the Study:
- To design and synthesize novel procaspase-3 activators with improved efficacy and reduced neurotoxicity for TNBC treatment.
- To evaluate the in vitro and in vivo anti-cancer activity and safety profile of newly developed compounds.
Main Methods:
- Ligand-based rational drug design and scaffold hybridization were employed to create novel compounds.
- In vitro assays assessed procaspase-3 activation, anti-proliferative activity, and cell migration inhibition.
- Density functional theory (DFT) calculations and in silico ADMET profiling were used for mechanistic and pharmacokinetic evaluation.
- In vivo studies evaluated anti-cancer efficacy and neurotoxicity in relevant models.
Main Results:
- Two lead compounds, F17 and F21, demonstrated superior in vitro procaspase-3 activation and potent anti-proliferative effects against TNBC cells (MDA-MB-231), outperforming the control PAC-1.
- DFT calculations revealed enhanced zinc-binding affinity and favorable electrostatic interactions for F17 and F21.
- In silico ADMET profiling indicated good drug-like properties, including low blood-brain barrier penetration.
- In vivo studies showed significant inhibition of cell migration and induction of apoptosis, with no observed neurotoxicity at therapeutic doses.
Conclusions:
- Novel procaspase-3 activators, F17 and F21, exhibit promising anti-cancer activity and a favorable safety profile for TNBC.
- Compound F21 is identified as a strong preclinical candidate, warranting further investigation for TNBC therapy.
- The study provides a rational design framework for developing targeted, neurotoxicity-sparing procaspase-3 activators.
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