<em>In vitro</em> characterization and rational analog design of a novel inhibitor of telomerase assembly in MDA MB 231 breast cancer cell line

Armando,Romina; Cabrera,Maia; Vilarullo,Roman; Chinestrad,Patricio; Maggio,Julian; Paderta,Camila; Lorenzano Menna,Pablo; Gomez,Daniel; Mengual Gómez,Diego

doi:10.3892/or.2022.8403

In vitro characterization and rational analog design of a novel inhibitor of telomerase assembly in MDA MB 231 breast cancer cell line

Authors:
- Romina Armando
- Maia Cabrera
- Roman Vilarullo
- Patricio Chinestrad
- Julian Maggio
- Camila Paderta
- Pablo Lorenzano Menna
- Daniel Gomez
- Diego Mengual Gómez
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Affiliations: Molecular Oncology Unit, Center of Molecular and Translational Oncology, Quilmes National University, Bernal, Buenos Aires B1876BXD, Argentina, Laboratory of Molecular Pharmacology, Quilmes National University, Bernal, Buenos Aires B1876BXD, Argentina
Published online on: September 13, 2022 https://doi.org/10.3892/or.2022.8403
Article Number: 188
Copyright: © Armando et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tumor cells have unlimited replicative potential, principally due to telomerase activity, which requires assembly of components such as dyskerin (hDKC1), human telomerase reverse transcriptase and human telomerase RNA (hTR). The present study aimed to develop novel inhibitors of telomerase to target the interaction between hTR and hDKC1. Based on docking‑based virtual screening, the candidates R1D2‑10 and R1D2‑15, which exert an in vitro inhibitory effect on telomerase activity, were selected. Human mammary adenocarcinoma MDA‑MB 231 cell line was selected to evaluate the treatment with the aforementioned compounds; the effect on telomere length was evaluated by qPCR, where both compounds caused telomere shortening. Furthermore, expression of genes related to apoptosis and senescence process, as well SA β galactosidase staining and caspase 3 activity. We determine that only compound R1D2‑10 showed and effect on the induction of these cellular processes. To identify a lead compound from R1D2‑10, 100 analogs were designed by LigDream server and then analyzed by AutoDock Vina and Protein‑Ligand Interaction Profile to calculate their docking energy and target interaction. Those with the best values and specific residue interactions were selected for in silico prediction of absorption, distribution, metabolism, excretion (ADME), off‑target interaction, toxicity and chemical diversity. A total of nine chemically different analogs was identified with higher docking affinity to the target, suitable ADME properties and not off‑target interaction and side effects. These results indicated R1D2‑10 and its analogs may serve as potential novel inhibitors of telomerase and antitumoral drugs in clinical use.

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