Generation and validation of a novel multitarget small molecule in glioblastoma
Aizpea Artetxe-Zurutuza1, Nerea Iturrioz-Rodriguez1, Joseba Elizazu1
1Cellular Oncology group, Biogipuzkoa (Biodonostia) Health Research Institute, San Sebastian, Spain.
Abstract:
The development of multitarget small molecules (MSMs) has emerged as a powerful strategy for the treatment of multifactorial diseases such as cancer. Glioblastoma is the most prevalent and malignant primary brain tumor in adults, which is characterized by poor prognosis and a high heterogeneity. Current standards of treatment present limited effectiveness, as patients develop therapy resistance and recur. In this work, we synthesized and characterized a novel multi-target molecule (named DDI199 or contilistat), which is a polyfunctionalized indole derivative developed by juxtaposing selected pharmacophoric moieties of the parent compounds Contilisant and Vorinostat (SAHA) to act as multifunctional ligands that inhibit histone deacetylases (HDACs), monoamine oxidases (MAOs) and cholinesterases (ChEs), and modulate histamine H3 (H3R) and Sigma 1 Receptor (S1R) receptors. DDI199 exerts high cytotoxic activity in conventional glioblastoma cell lines and patient-derived glioma stem cells in vitro. Importantly, it significantly reduces tumor growth in vivo, both alone and in combination with temozolomide (TMZ). The comparison with SAHA showed higher target specificity and antitumor activity of the new molecule. Transcriptomic and proteomic analyses of patient-derived glioma stem cells revealed a deregulation in cell cycle, DNA remodeling and neurotransmission activity by the treatment with DDI199. In conclusion, our data reveal the efficacy of a novel MSM in glioblastoma pre-clinical setting.
Insights
A novel multitarget small molecule, DDI199, shows significant efficacy against glioblastoma by inhibiting multiple targets. This new compound effectively reduces tumor growth in preclinical models, offering a promising new therapeutic strategy.
Area of Science:
- Oncology
- Neuroscience
- Medicinal Chemistry
Background:
- Glioblastoma is a highly aggressive brain tumor with poor outcomes and limited treatment options.
- Existing therapies often lead to resistance and recurrence, necessitating novel therapeutic approaches.
- Multitarget small molecules (MSMs) offer a promising strategy for complex diseases like cancer.
Purpose of the Study:
- To synthesize and characterize a novel MSM, DDI199 (contilistat), for glioblastoma treatment.
- To evaluate the in vitro and in vivo efficacy of DDI199 against glioblastoma.
- To investigate the molecular mechanisms underlying DDI199's antitumor activity.
Main Methods:
- Synthesis and characterization of DDI199, a polyfunctionalized indole derivative.
- In vitro cytotoxicity assays on glioblastoma cell lines and patient-derived glioma stem cells.
- In vivo tumor growth inhibition studies in glioblastoma models, alone and with temozolomide.
- Transcriptomic and proteomic analyses to elucidate molecular targets and pathways.
Main Results:
- DDI199 demonstrated high cytotoxic activity against glioblastoma cells in vitro.
- Significant reduction in tumor growth was observed in vivo with DDI199 treatment.
- DDI199 exhibited superior target specificity and antitumor activity compared to Vorinostat (SAHA).
- Molecular analyses revealed DDI199 modulates cell cycle, DNA remodeling, and neurotransmission pathways.
Conclusions:
- DDI199 is a novel, effective MSM for glioblastoma.
- The compound shows promise as a new therapeutic agent in preclinical settings.
- DDI199's multitargeting approach warrants further investigation for glioblastoma treatment.
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