Non peptidic 14-3-3 inhibitors and their use
The invention refers to compounds with inhibitory activity against 14-3-3 proteins and their use in the treatment of tumors, in particular chronic myeloid leukemia. The invention also provides methods for the identification of 14-3-3 protein inhibitors.
Tyrosine kinase inhibitors, such as Imatinib, are currently used as effective and frontline therapy for chronic-phase of chronic myeloid leukemia (CML). Despite the generally positive response to treatment, Imatinib resistance represents a serious clinical problem in patients expressing the oncogenic Bcr-Abl fusion gene. The 14-3-3 protein family of regulatory molecules control the oncogenic properties of Abl by binding and sequestering this kinase in the cytoplasm. The invention discloses novel non-peptidic 14-3-3 binding molecules based on the crystallographic structure of human 14-3-3σ isoform complexed with a mode-1 phosphopeptide. Used in farmaceutical compositions, these molecules represent therefore a helpful anti-tumor strategy to enhance the effects of traditional inhibitors of the oncogenic Bcr-Abl protein.
- In-silico screening of molecules;
- 14-3-3σ ligand coordinates;
- Treatment of Imatinib-resistant chronic myeloid leukemia.
- Docking algorithm;
- Molecular dynamics simulation,
- Nuclear cAbl relocation;
- Apoptotic pathway induction.