In his doctoral study, Suresh Palanivel identifies a novel synthetic alkylamino phenolic derivative, as an Epidermal Growth Factor Receptor targeted therapy hampering EGFR downstream signaling cascade that favors breast cancer proliferation.
Breast cancer is the most common malignancy in women worldwide and more than 5000 new cases were diagnosed in Finland in 2020. Recent drug discovery approaches have contributed to developing more efficient therapeutic agents for treating breast cancer patients. However, therapeutic resistance mechanisms of breast cancer led to treatment failure and hence require urgent attention for the development of new drugs. Among several treatment modalities, targeted therapies provide an efficient treatment strategy to cure breast cancer.
Advances in anticancer drug discovery using broad-spectrum drugs, such as substituted alkylamino phenolic rings or indoline rings, have emerged as promising molecules. Thus, investigating the targeted binding and downstream signaling effects of these compounds in inducing apoptosis would evade the significant challenges in current breast cancer therapies. Suresh Palanivel performed an extensive study to identify the potential phenolic compound that interacts with EGFR and its downstream signaling effects in inducing apoptosis.
Palanivel investigated three newly synthesized alkylamino phenolic derivatives for their anti-breast cancer activity. Each of the derivatives has been evaluated using the multi-disciplinary approach for their cytotoxicity, apoptotic activity, caspase activity, and DNA fragmentation that accounts for cell death. He also performed Real-time PCR analysis, molecular docking analysis, and molecular dynamic simulation to identify the drug’s potential interaction and stability with compounds targeting EGFR. The physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of all the derivatives were also evaluated using absorption, distribution, metabolism, and excretion (ADME) profiling.
His research investigation identified that, among all the derivatives analyzed, HNPMI was found to be the potential derivative possessing the highest cytotoxic effect. HNPMI exhibited the least binding energy with the highest docking score than the EGFR ligand, thus proving HNPMI as a potential target of EGFR. Further, HNPMI caused inter-nucleosomal DNA fragmentation in the breast cancer cells exhibiting the characteristic features of apoptosis causing cell death. Additionally, EGFR targeted HNPMI induces caspase-mediated apoptosis by regulating the EGFR downstream signaling genes, phosphoinositide 3-kinases, and ribosomal protein S6 kinase beta-1. The molecular dynamics simulation suggests that the protein-inhibitor complexes are stable with stronger binding interactions between the inhibitor and the protein and thus proved HNMPI as the best complex with the lowest RMSD and stable interactions. This derivative also has good pharmacokinetic properties and obeyed the drug likeliness rules.
“Overall, HNPMI, an EGFR inhibitor, functions as a potential anti-breast cancer compound. Therefore, alkylamino phenolic derivative, HNMPI could be used as a novel targeted therapy to combat breast cancer”, Suresh Palanivel says.
The study was carried out in the Molecular Signaling Group, under the supervision of Docent Meenakshisundaram Kandhavelu, University lecturer, and Professor Olli Yli-Harja, Computational Systems Biology Group.
The doctoral dissertation of M.Sc. (Tech) Suresh Palanivel, in the field of Biomedical Sciences and Engineering, entitled “Evaluation of cytotoxic effects and underlying mechanism of phenolic compounds on breast cancer cell lines” will be publicly examined in the Faculty of Medicine and Health Technology of Tampere University at 15.00 pm EEST, Tuesday 31st May 2022. The Opponent will be Professor Raghu Sinha from the Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, Pennsylvania, USA. The Custos will be Professor Olli Yli-Harja, from the Faculty of Medicine and Health Technology, Tampere University.
The dissertation is available online at the http://urn.fi/URN:ISBN:978-952-03-2447-6
The event can be followed via Zoom connection.
Photo: Lauri Koskela