A novel Notch-targeted therapeutic approach in multiple myeloma based on small molecules disrupting Notch-Jagged interaction

Multiple myeloma (MM) is an incurable hematological malignancy characterized by MM cells accumulation in the bone marrow (BM) promoting tumor survival and drug resistance. The oncogenic Notch signaling plays a crucial role in MM. The overexpression of Notch ligands, Jagged1 and 2 leads to aberrant Notch activation in MM resulting in tumor growth and stimulating MM cells to establish pathological interactions with BM. These effects can be interfered by knocking-down Jagged1 and 2 in MM cells. Here we provide a rationale for an unprecedented therapeutic approach targeting Notch-Jag interaction in MM based on small molecules disrupting this interaction by exclusive targeting only Notch members dysregulated in MM. This will avoid a toxicity caused by pan-Notch inhibitors, γ-secretase inhibitors (GSIs). We have identified in silico 100 top-scoring small molecules able to disrupt Notch-Jagged complex by screening the Asinex library (450000 compounds). The inhibitory effect of two compounds, ANJ121 and ANJ122, on Notch transcriptional activity was analyzed by a Notch responsive reporter assay in HEK293T cells. The compounds efficacy in inhibiting Notch activity was comparable to GSIs. Moreover, the compounds effectively reduced the ability of MM-derived Jagged ligands to activate Notch signaling in nearby BM stromal cells. Finally, we verified that the compounds induced dose-dependent cell growth inhibition comparable to GSIs. These findings suggest that the proposed approach promises to be effective to overcome the effect of Notch activation in MM and the BM stromal cells. This prompts us to expand and optimize candidate compounds to provide a complete preclinical package.