New pyrrole derivatives for the treatment of glioblastoma and chronic myeloid leukemia

Glioblastoma multiforme (GBM), is one of the most aggressive malignant brain tumors in humans. Long-term survivors of glioblastoma multiforme are at high risk of developing second primary neoplasms, including leukemia. Chronic myeloid leukemia (CML) and GBM patients are both treated with classic tyrosine kinase inhibitors (TKIs), such as imatinib mesylate. The use of imatinib mesylate, is strongly discouraged since this treatment causes a tremendous increase of tumor and stem cell migration and invasion. We aimed to develop agents useful for the treatment of patients with GBM and CML using an alternative mechanism of action from the TKIs, specifically based on the inhibition of tubulin polymerization. 3-Aroyl-1,4-diarylpyrrole RS5156 (1) is a potent inhibitor of tubulin polymerization and cancer cell growth by binding the colchicine site of tubulin. The aim of the present research project is that to fully evaluate the potential of ARDAP derivatives in treatment of CML. Starting from the ARDAP derivatives, characterized by the presence of one or two aminophenyl groups at position 1 and 4, we aimed to improve multiple parameters, such as potency, metabolic stability and blood-brain barrier (BBB) permeability. We thus replaced the 4-aminophenyl group with five- and six- membered bioisosteric heterocycles, while retaining the important methyl and fluoro substituents on the 1-phenyl ring (Chart 1). [1] We synthesized compounds 2-25 which were shown to inhibit tubulin polymerization with IC50 values at submicromolar concentrations. In particular, compounds 7 and 14 were found to be more potent inhibitors of tubulin polymerization, with IC50 values of 0.39 and 0.38 mM, respectively. Two human glioblastoma cell lines, U343MG and U87MG, were select to evaluate the potential of two of 7 and 25. Compounds 7 and 25 were thus compared with the TKIs imatinib (IM) and third-generation ponatinib (PN) in the Bcr-Abl-expressing KU812 cells, in the IM-sensitive KBM5 cells and in the IM-resistant KBM5-T315I cells expressing the threonine for isoleucine mutation at position 315 of the oncoprotein. The IC50 values of both compounds were at least one order of magnitude superior to imatinib. Taking into account these very promising data the activity of ARDAP 7 against the U87MG human glioma cell line was also tested in vivo, where significantly inhibited GBM cancer cell proliferation, tumorigenesis and tumor angiogenesis. References [1] M. Puxeddu, H. Shen, R. Bai, A. Coluccia, M. Bufano, M. Nalli, J. Sebastiani, D. Brancaccio, E. Da Pozzo, C. Tremolanti, C. Martini, V. Orlando, S. Biagioni, M. S. Sinicropi, J. Ceramella, D. Iacopetta, A. M. L. Coluccia, E. Hamel, T. Liu, R. Silvestri, G. La Regina. Discovery of pyrrole derivatives for the treatment of glioblastoma and chronic myeloid leukemia. Eur. J. Med. Chem. 2021, e113532.