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

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

Targeting beta-catenin and dishevelled protein as a synergistic strategy against colorectal cancer

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.

Sulfonamide inhibitors of beta-catenin signaling with different output on c-MYC as anticancer agents

Laura Di Magno, Fiorella Di Pastena, Michela Puxeddu, Giuseppe La Regina, Antonio Coluccia, Alessia Ciogli, Simone Manetto,Marella Maroder, Gianluca Canettieri, Romano Silvestri, Marianna Nalli. ChemMedChem 202015, 2264-2268.

The Wnt/b-catenin pathway is often found deregulated in cancer. The aberrant accumulation of b-catenin in the cell nucleus results in the development of various malignancies. Specific drugs against this signaling pathway for clinical treatments have not been approved yet. Here we report inhibitors of b-catenin signaling of potential therapeutic value as anticancer agents. Compound 14 inhibits the effect on Wnt reporter with IC50 of 7.0 μM, significantly reduces c-MYC levels, inhibits HCT116 colon cancer cell growth with IC50 of 20.2 mM, does not violate the Lipinski and Veber rules and shows predicted Caco-2 and MDCK cell permeability Papp >500 nm/s. Compound 14 seems to have potential for the development of new anticancer therapies