B-cell lymphoma 6 (BCL6) is a transcriptional factor that expresses in lymphocytes and regulates the differentiation and proliferation of lymphocytes. Therefore, BCL6 is a therapeutic target for autoimmune diseases and cancer treatment. This report presents the discovery of BCL6-corepressor interaction inhibitors by using a biophysics-driven fragment-based approach. Using the surface plasmon resonance (SPR)-based fragment screening, we successfully identified fragment 1 (SPR K = 1200 μM, ligand efficiency (LE) = 0.28), a competitive binder to the natural ligand BCoR peptide. Moreover, we elaborated 1 into the more potent compound 7 (SPR K = 0.078 μM, LE = 0.37, cell-free protein-protein interaction (PPI) IC = 0.48 μM (ELISA), cellular PPI IC = 8.6 μM (M2H)) by a structure-based design and structural integration with a second high-throughput screening hit.

Three novel hybrid polyketide-terpenoid metabolites were isolated from a Penicillium minioluteum strain. Their structures were determined by NMR spectroscopic analyses and X-ray crystallography. The proposed biosynthetic pathway including a unique retro-Claisen migration of methyl carbonate correlates the three compounds with berkeleydione and berkeleytrione.

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TAK-925, a potent, selective, and brain-penetrant orexin 2 receptor (OX2R) agonist, [methyl (2 R ,3 S )-3-((methylsulfonyl)amino)-2-((( cis -4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, 16 ], was identified through the optimization of compound 2 , which was discovered by a high throughput screening (HTS) campaign. Subcutaneous administration of compound 16 produced wake-promoting effects in mice during the sleep phase. Compound 16 (TAK-925) is being developed for the treatment of narcolepsy and other related disorders.

Terpenes U 0200Three New Polyketide-Terpenoid Hybrids from Penicillium sp. -[22-epoxyberkeleydione (I), miniolutelide A (II) and miniolutelide B (III)]. -(IIDA, M.; OOI, T.; KITO, K.; YOSHIDA, S.; KANOH, K.; SHIZURI, Y.; KUSUMI*, T.; Org. Lett. 10 (2008) 5, 845-848; Inst. Health Biosci., Grad. Sch., Univ. Tokushima, Tokushima 770, Japan; Eng.) -Lindner 30-186