Treatment of chronic myeloid leukemia by inhibition of tubulin polymerization

Treatment of chronic myeloid leukemia by inhibition of tubulin polymerization

3-Aroyl-1,4-diarylpyrrole RS5156 is a potent inhibitor of tubulin polymerization and cancer cell growth by binding the colchicine site of tubulin, recently developed by our research group. RS5156 inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from chronic myeloid leukemia (CML) patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib-sensitive KBM5-WT or imatinib-resistant KBM5-T315I mutation. The same compound minimally affected the proliferation of normal blood cells, indicating that it may be a promising hit compound to overcome broad TKI resistance in relapsed/refractory CML patients.

Taking into account these very promising data, the aim of the present research project is that to fully evaluate the potential of ARDAP derivatives in treatment of CML. In fact, the activity of colchicine binding site agents in CML has not been deeply explored. In addition, despite the very promising anti-leukemia activity, previuosly reported RS5156 suffers from some non-optimal pharmacokinetic properties, such as low aqueous solubility and low metabolic stability.

Preliminary results suggested that the introduction of a heterocycle at position 4 of the pyrrole nucleus boost both inhibition of tubulin polymerization and anti-leukemia activity by additional favourable interactions into the colchicine binding site of tubulin. Aims of the present research project are: 1. design of the new compounds and molecular modelling studies; 2. chemical synthesis of the most promising compounds; 3. biological evaluation of the newly prepared compounds as inhibitors of tubulin polymerization and [3H]colchicine binding; 4. biological evaluation of the most active compounds as inhibitors of TKI-sensitive or TKI-resistant CML cell lines as single agent or in combination with other TKIs, such as imatinib (first generation), dasatinib, nilotinib, and bosutinib (second generation), and ponatinib (third generation), using normal blood cells as control; 5. further biological characterization of the selected compounds in leukemia cells in terms of cell morphological features, cell cycle distribution, apoptosis study, caspase-3 activity, mitochondrial permeability transition detection, phospho-activation and its signal transduction; 6. in vitro and in vivo pharmacokinetic characterization of the selected compounds. The final goal of the present research project is the identification of one or more lead compounds with potent anti-leukemia activity and improved pharmacokinetic profile for the treatment of relapsed/refractory CML patients.

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