Ricerc@Sapienza

3-Aroyl-1,4-diarylpyrroles are potent inhibitors of tubulin polymerization and cancer cell growth by binding the colchicine site of tubulin, recently developed by our research group. The most potent derivative 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(IM)-sensitive KBM5-WT or IM-resistant KBM5-T315I mutation. The same derivative minimally affected the proliferation of normal blood cells, indicating that it may be a promising hit compound to overcome broad tyrosine kinase inhibitor (TKI) resistance in relapsed/refractory CML patients.
Preliminary results suggested that the introduction of a heterocycle at position 4 of the pyrrole ring increase both tubulin polymerization and antileukemia activity. The present research aims to identify one or more new lead compounds endowed with improved biological and pharmacokinetic profile by introducing on the pyrrole ring different heterocycles at position 4 and substituting the phenyl ring at position 1 with electron donating and withdrawing groups.
All the newly compounds will be tested for their ability to inhibit tubulin polymerization, binding of colchicine to tubulin and cancer cell growth. The most active compounds as single agent or in combination with other TKIs will be then investigated for efficacy with BCR/ABL-expressing cells established in vitro from CML patients in blast crisis (KU812 and LAMA 84), using normal blood cells as control. The analysis will be extended to proliferation and viability of IM-sensitive KBM5-WT and IM-resistant KBM5-T315I cells. The anticancer activity of the same compounds will be evaluated in other TKI-resistant leukemia cell lines. The biological profile of the new derivatives will be further investigated in terms of influence on mitochondrial functions, effects on cell life/death processes and pharmacokinetic profile.