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Abstract Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 under investigation for the treatment of cancer, including non‐Hodgkin's lymphomas and solid tumors. Itraconazole and fluconazole are antifungal medications often used as typical inhibitors of cytochrome P450 3A (CYP3A [itraconazole and fluconazole]) and P‐glycoprotein (P‐gp [itraconazole]) in drug–drug interaction studies. Valemetostat is a substrate of CYP3A and P‐gp in vitro. This phase I, open‐label, single‐sequence crossover study (JapicCTI‐183902) assessed the pharmacokinetics (PK) of valemetostat when co‐administered with itraconazole (a strong CYP3A inhibitor and P‐gp inhibitor) or fluconazole (a moderate CYP3A inhibitor) in healthy Japanese male participants 20–45 years of age. Participants were equally allocated to receive two doses of valemetostat 25 mg, once alone and once with either itraconazole or fluconazole (400‐mg induction and 200‐mg once daily maintenance). Valemetostat PK parameters with versus without itraconazole or fluconazole were compared using analysis of variance models. Overall, 32 participants were enrolled. Co‐administration with itraconazole increased valemetostat peak concentration (Cmax) by 2.9‐fold and area under the plasma concentration–time curve extrapolated to infinity (AUCinf) by 4.2‐fold compared with valemetostat alone. When co‐administered with fluconazole, the Cmax and AUCinf of valemetostat were each increased by 1.6‐fold. No treatment‐related or grade ≥3 adverse events were reported. Appropriate valemetostat dose reductions are warranted when used concomitantly with strong CYP3A and P‐gp dual inhibitors.

The existing methods for exosome isolation, such as ultracentrifugation, size exclusion, and affinity separation, suffer from some limitations. Herein, we aimed to develop temperature-modulated exosome-capturing materials using thermoresponsive polymers and peptides with affinity for exosomes. Poly(2-hydroxyethyl methacrylate-co-propargyl acrylate)-b-poly(N-isopropylacrylamide) (P(HEMA-co-PgA)-b-PNIPAAm) was grafted on silica beads via a two-step process of activator regenerated by electron transfer atom transfer radical polymerization. Peptides with affinity for exosomes were conjugated to the propargyl group of the bottom P(HEMA-co-PgA) segment of the copolymer via a click reaction. The prepared copolymer-grafted beads were characterized by elemental analysis, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy, gel permeation chromatography, and the turbidity of the polymer solution. Results indicated that the copolymer and peptide were successfully modified on the silica beads. Exosomes from SK-BR-3 ​cells, a human breast cancer cell line, were selectively captured on the prepared beads at 37 ​°C, as the upper PNIPAAm segment shrank and the affinity between the peptide and exosome was enhanced. Upon lowering the temperature to 4 ​°C, the captured exosomes were released from the copolymer brush because of the extension of the PNIPAAm segment that reduced the affinity between peptides and exosomes. These findings demonstrated that the prepared copolymer brush-grafted silica beads can capture and release targeted exosomes via temperature modulation. Taken together, the developed copolymer brush-grafted silica beads would be useful for the separation of exosomes using simple procedures such as temperature modulation.

A novel stereoisomer of eushearilide, 23-demethyleushearilide, was synthesized, and the structure−activity relationships of this compound along with known eushearilide stereoisomers were investigated in order to design novel lead compounds for the treatment of fungal infections. It was discovered that all of these congeners, together with the natural product, exhibited a wide range of antimicrobial activity against not only fungi but also against bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).