Abstract Number: PB0754
Meeting: ISTH 2021 Congress
Theme: Role of Hemostatic System in Cancer, Inflammation and Immunity » Platelets and Cancer
Background: Nilotinib is a Bcr-Abl tyrosine kinase inhibitor used to treat various malignancies. We had previously demonstrated that Nilotinib exhibits an antiplatelet activity (Pantazi D, et al. DDDT. 2019;13:4225-38).
Aims: We synthesized new Nilotinib analogues in an effort to improve the drug antiplatelet potency, while maintaining or enhancing its cytostatic properties.
Methods: Three novel Nilotinib analogues, containing the following modifications at the final phenyl ring, were designed, synthesized and fully characterized:
1. In all analogues, the CF3 group at the 5-position was removed, whereas the 4-methylimidazolyl ring at the 3-position was replaced by a NO2 group.
2. A halogen atom, F or a Cl, was incorporated at the 4-position (analogue-2 and analogue-3, respectively). Light Transmittance Aggregometry (LTA) in the presence of Nilotinib or its analogues was performed in platelet-rich plasma (PRP) activated with Arachidonic acid (AA), ADP or TRAP-6. Confluent hepatoma HepG2 cells in culture were incubated for 48h with Nilotinib or its analogues. The cell cycle was studied by Flow Cytometry, after cell staining with propidium iodide. Data are expressed as means±SD and statistical analysis was performed by Two-way ANOVA.
Results: Nilotinib and its analogues, significantly inhibited platelet aggregation induced by AA, the analogues 1 and 2 being more potent than Nilotinib. The IC50 values and the threshold concentrations are shown in Table 1. A slight non-significant inhibition by all compounds was observed when ADP or TRAP-6 were used as agonists. In HepG2 cells, Nilotinib significantly increased the %gated cells in M1 phase, whereas all analogues reduced the %gated cells in M1 phase and increased the %gated cells in M3 phase (Table 2).
Table 1
Compounds | IC50 values (μΜ) | Threshold concentration (μΜ) |
Nilotinib | 3.94 ± 2.09 | 10.00 ± 2.83 |
Analogue-1 | 1.50 ± 1.08 | 2.87 ± 1.31 |
Analogue-2 | 0.57 ± 0.21 | 3.00 ± 1.41 |
Analogue-3 | 5.45 ± 6.11 | 8.33 ± 10.12 |
Table 2
% Gated cells | |||||
Cell cycle phases | Control | Nilotinib (10μΜ) |
Analogue-1 (10μΜ) | Analogue-2 (10μΜ) | Analogue-3 (10μΜ) |
M1(G0/G1) | 85.14 ± 2.84 | 87.36 ± 2.66* | 79.96 ± 4.53*,** | 81.59 ± 1.19*,** | 78.35 ± 3.51*,** |
M2(S) | 4.62 ± 1.01 | 3.93 ± 1.05 | 5.38 ± 1.19 | 5.62 ± 0.27 | 6.39 ± 1.03** |
M3(G2/M) | 9.84 ± 1.92 | 8.18 ± 1.85 | 13.84 ± 3.03*,** | 12.25 ± 0.85*,** | 13.26 ± 2.20*,** |
*p<0.05 and **p<0.05 compared with control and Nilotinib, respectively
Conclusions: There is considerable potential to develop synthetic Nilotinib analogues with potent antiplatelet activity and improved cytostatic properties to treat cancer and to prevent cancer-associated thrombosis.
To cite this abstract in AMA style:
Pechlivani LM, Ntemou N, Voulgari P, Pantazi D, Skobridis K, Tselepis AD. Antiplatelet and Cytostatic Properties of Nilotinib Synthetic Analogues [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/antiplatelet-and-cytostatic-properties-of-nilotinib-synthetic-analogues/. Accessed March 22, 2024.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/antiplatelet-and-cytostatic-properties-of-nilotinib-synthetic-analogues/