The proteasome is the main non-lysosomal proteolytic complex, an already validated target for the treatment of multiple myeloma and other human diseases, such as Chagas disease, leishmaniasis and inflammation. Finding substances capable of inhibiting the proteasome complex constitute a sounding strategy for the finding of antitumoral drugs. Organic and water-soluble extracts of different species of marine sponges were obtained and fractionated. Fractions were submitted to proteasome assay and twenty-two samples showed activity. This samples were prioritezed by HPLC-UV-MS and UPLC-HRMS/MS (QToF) analysis. MS/MS data was applied to molecular networking approach and dereplication using GNPS plataform. Dereplication and chemical space analysis allow us to avoid redundance and rediscovery. Moreover, results have indicated that several compounds probably are not described in the literature yet. Hot hits include marine sponges that are source of polyketides, a class of metabolites for which proteasome inhibition has not yet been previously described.