Discovery of novel pyrrole derivatives as anti-glioblastoma and anti-chronic myeloid leukemia agents

Long-term survivors of glioblastoma multiforme (GBM) are at high risk of developing second primary neoplasms, including leukemia. For these patients, the use of classic tyrosine kinase inhibitors (TKIs), such as imatinib mesylate, is strongly discouraged since this treatment causes a tremendous increase of tumour and stem cell migration and invasion. We aimed to develop agents useful for the treatment of patients with GBM and chronic myeloid leukemia (CML) using an alternative mechanism of action from the TKIs, specifically based on the inhibition of tubulin polymerization. [1] (4-(Thiophen-3-yl)-1-(p-tolyl)-1H-pyrrol-3-yl)(3,4,5-trimethoxy-phenyl)methanone (RS5645) and (1-(4-fluorophenyl)-4-(pyridin-4-yl)-1H-pyrrol-3-yl) (3,4,5-trimethoxyphenyl)methanone (RS5893) derivatives, as planned, not only inhibited tubulin polymerization, but also inhibited the proliferation of both GMB and CML cells, including those expressing the T315I mutation, at nanomolar concentrations. In in vivo experiments in BALB/cnu/nu mice injected subcutaneously with U87MG GBM cells, RS5645 significantly inhibited tumour growth, tumorigenesis, and 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 and G. La Regina Eur. J. Med. Chem. 221 (2021) art. no. e113532.