Screening the Irish Marine Biorepository Identifies a New Bryostatin Analog as Potent Inhibitor of Activated B-Cells...

Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive cancer with poor response to standard chemotherapy. In search of new therapeutic leads, a library of 435 fractions prepared from the Irish marine biorepository was screened against 2 ABC-DLBCL cell lines (TMD8 and OCI-Ly10) and a non-cancerous control cell line (CB33). Active fractions are prioritized based on potency and selectivity. Among them, fractions from the nudibranch Antiopella cristata and the ascidian Diplosoma listerianum exhibit the most potent and selective cytotoxicity. Bioassay-guided fractionation of D. listerianum led to the identification of the known loliolide and epiloliolide. On the other hand, A. cristata yielded several bryostatin analogs, including bryostatin 13 and a new natural product, its 18-demethylated analog. Both compounds demonstrated nanomolar cytotoxicity against ABC-DLBCL cell lines with minimal activity in CB33. Transcriptomic profiling showed significant gene expression changes, particularly for the 18-demethylated analog, implicating modulation of key signaling pathways. This study identifies A. cristata as a novel and highly enriched source of bioactive bryostatins and supports the dietary sequestration hypothesis in nudibranchs, highlighting the value of marine invertebrates as reservoirs of selective anticancer agents for drug discovery.