Bioassay-guided fractionation of two cyanobacterial extracts from Papua New Guinea has yielded hoiamide D in both its carboxylic acid and conjugate base forms. Hoiamide D is a polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS)-derived natural product that features two consecutive thiazolines and a thiazole, as well as a modified isoleucine residue. Hoiamide D displayed inhibitory activity against p53/MDM2 interaction (EC(50)=4.5 μM), an attractive target for anticancer drug development.