期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：12
页码：E1471-E1479
DOI：10.1073/pnas.1417832112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDespite dramatically improved therapeutic properties of single enantiomer drugs over the racemic mixtures, numerous drugs and drug candidates are still being developed and sold as racemates, including the class of immunomodulatory drugs derived from thalidomide. The chiral center of these thalidomide analogs is chemically unstable, resulting in interconversion of the enantiomers both in vitro and in vivo. Through stabilization of the chiral center with deuterium, we show for the first time, to our knowledge, that the in vitro antiinflammatory and in vivo antitumorigenic activities of a thalidomide analog currently in clinical development (CC-122) are caused exclusively by one enantiomer. Our findings enable the development of improved thalidomide analogs as therapeutics following stated regulatory guidance for the development of single enantiomers. Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety. Herein, we show that replacement of the exchangeable hydrogen at the chiral center with deuterium allows the stabilization and testing of individual enantiomers for two thalidomide analogs, including CC-122, a compound currently in human clinical trials for hematological cancers and solid tumors. Using "deuterium-enabled chiral switching" (DECS), in vitro antiinflammatory differences of up to 20-fold are observed between the deuterium-stabilized enantiomers. In vivo, the exposure is dramatically increased for each enantiomer while they retain similar pharmacokinetics. Furthermore, the single deuterated enantiomers related to CC-122 exhibit profoundly different in vivo responses in an NCI-H929 myeloma xenograft model. The (-)-deuterated enantiomer is antitumorigenic, whereas the (+)-deuterated enantiomer has little to no effect on tumor growth. The ability to stabilize and differentiate enantiomers by DECS opens up a vast window of opportunity to characterize the class effects of thalidomide analogs and improve on the therapeutic promise of other racemic compounds, including the development of safer therapeutics and the discovery of new mechanisms and clinical applications for existing therapeutics.
关键词：thalidomide ; enantiomer ; deuterium ; CC-122 ; cancer
