PB0755 - Synthetic Bcr-Abl tyrosine kinase inhibitors; their profile towards antiplatelet activity and cancer cell functionality

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Co-Author(s)

LP

Louisa M. Pechlivani, MSc, PhD candidate

Chemist, PhD Candidate
Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece
Ioannina, Ioannina, Greece
NN

Nikoleta Ntemou

Chemist, PhD
Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece
Ioannina, Ioannina, Greece
PV

Pinelopi Voulgari

Chemist, PhD
Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece
Ioannina, Ioannina, Greece
DP

Despoina Pantazi

biologist
University Hospital of Ioannina
Ioannina, Attiki, Greece
KS

Konstantinos Skobridis

Professor of Organic Chemistry, PhD
Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece
Ioannina, Ioannina, Greece

Presenting Author(s)

AT

Alexandros D. Tselepis, MD, PhD

Emeritus Professor of Biochemistry-Clinical Chemistry, MD, PhD
Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece
Ioannina, Ioannina, Greece

Background: Bcr-Abl tyrosine kinase inhibitors are used to treat various malignancies and we had previously demonstrated that they also exhibit antiplatelet activity (Pantazi D, et al. DDDT. 2019;13:4225-38).

Aims: We synthesized new inhibitors and evaluated their profile towards cancer cell functionality and transition, as well as their antiplatelet potency.

Methods: Three novel Bcr-Abl tyrosine kinase inhibitors were designed, synthesized and fully characterized. They differentiate at their final phenyl ring, having a halogen atom, F or Cl at the 4th position (Figure). Light Transmittance Aggregometry in the presence of these inhibitors was performed in platelet-rich plasma activated with Arachidonic acid (AA). Confluent hepatoma HepG2 cells in culture were incubated for 48h with the synthetic compounds and the cell apoptosis was studied by Flow Cytometry after cell staining with Propidium iodide and Annexin-V. To evaluate the epithelial–mesenchymal transition (EMT) we quantified the expression of adhesion proteins, E-cadherine and N-cadherine by Western blot, while the cell functionality and migration was studied using the Boyden chamber assay.

Results: Compound-1, -2 and -3 significantly inhibited platelet aggregation induced by AA to a similar extent and the IC50 values were 1.501.08μΜ, 0.940.66μΜ and 1.730.73μΜ, respectively. In HepG2 cells, the compound-3 exhibited the strongest apoptotic effect (Table). Furthermore, all compounds decreased the expression of E-cadherine by 51.78%, 25.07% and 82.73%, and N-cadherine by 32.16%, 65.24% and 48.17%, respectively and inhibited the migration of HepG2 cells by 25.42%, 17.37% and 25.98%, respectively.

Conclusion(s): Compounds-1 and -3 had potent antiplatelet activity and similar inhibitory effects towards cancer cell functionality and transition. Their structure could set the example to develop new Bcr-Abl tyrosine kinase inhibitors in order to efficiently treat cancer and effectively prevent cancer-associated thrombosis.