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 tumor 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. Compounds 7 and 25, as planned, concentration of 100 mM.
European Journal of Medicinal Chemistry 221 (2021) 113532
Research project funded by AIRC.
We aim to obtain compounds inhibitors of the Wnt/β-catenin pathway with efficacy for CRC cancer cells. The identified modulators have to be endowed with physicochemical and ADME properties required for drug candidates.
The experimental plan is therefore: (1) to test the effect of the different modulators on the Wnt/TCF signaling and to perform functional analyses by using reporter vectors and endogenous targets; (2) to test the effect of the different inhibitors of NHERF1 on DVL; (3) refinement of pharmacophores by means of the Wnt/β-Catenin and DVL structural information; (4) virtual screening studies of compound libraries, selection and synthesis of analogues; (5) in vitro test of Wnt-β/TCF and DVL modulators; (6) CRC inhibition by singly and in drug combination; (7) optimization of the drug-like properties of most powerful drugs; (8) in vivo test in APCMin/+ mice.
We expect to identify compounds as potential drug for CRC treatment and combinations thereof for CRC in vivo studies.