Penicacid G, a C-4′-Oxidized Mycophenolic Acid Derivative from Marine-Derived Penicillium sp. 1901NT-2.53.1, Selectively Inhibits ERα-Positive Breast Cancer Cells Through ERα Pathway Engagement

Background: Mycophenolic acid (MPA) is an IMPDH inhibitor used clinically as an immunosuppressant, but its antiproliferative potency is offset by immune toxicity. We previously identified marine-derived MPA analogues as candidate estrogen receptor α (ERα) ligands. Here, we tested whether penicacid G (PG), a C-4′-oxidized MPA derivative from the marine fungus Penicillium sp. 1901NT-2.53.1, exerts ERα-dependent antiproliferative activity against ER-positive breast cancer cells. Methods: Molecular targets were predicted with TargetNet and OCHEM QSAR models; ERα binding was modeled by docking (PDB 3UUD) and 100 ns molecular dynamics. Cytotoxicities of PG, 4′-hydroxy-MPA, and MPA were determined in MCF-7, MDA-MB-231, H9c2, and MonoMac-1 cells. ERα dependence was interrogated by 4-hydroxytamoxifen (4-OHT) competition, clonogenic assay, ERα monomer/dimer analysis, qPCR of ER-regulated transcripts, cell-cycle flow cytometry, and LINCS L1000 analysis. Results: PG docked into the ERα ligand-binding pocket (−7.7 kcal/mol) and remained stably bound over 100 ns. PG reduced MCF-7 viability at 1 μM (−19.4%) without affecting MDA-MB-231, H9c2, or MonoMac-1 cells (IC50 > 100 μM) and inhibited MCF-7 colony formation (IC50 3.1 μM). Its effect was attenuated by 4-OHT and accompanied by altered ERα monomer/dimer ratios, rapid PHB2 upregulation, and IGFBP4 suppression, indicating ERα pathway engagement. In contrast, MPA inhibited both cancer cell lines, was not blocked by 4-OHT, and its LINCS L1000 profile suggests indirect antagonism of ER-dependent transcription secondary to nucleotide depletion. Conclusions: Penicacid G is an ERα-engaging MPA analogue that selectively impairs ER-positive breast cancer cell proliferation while sparing monocytic immune cells, representing a promising ERα-targeted lead scaffold.