title: Identification of the antineoplastic agent 6-mercaptopurine as an activator of the orphan nuclear hormone receptor Nurr1.
abstract: The purine anti-metabolite 6-mercaptopurine is one of the most widely used drugs for the treatment of acute childhood leukemia and chronic myelocytic leukemia. Developed in the 1950s, the drug is also being used as a treatment for inflammatory diseases such as Crohn's disease. The antiproliferative mechanism of action of this drug and other purine anti-metabolites has been demonstrated to be through inhibition of de novo purine synthesis and incorporation into nucleic acids. Despite the extensive clinical use and study of 6-mercaptopurine and other purine analogues, the cellular effects of these compounds remain relatively unknown. More recently, purine anti-metabolites have been shown to function as protein kinase inhibitors and to regulate gene expression. In an attempt to find small molecule regulators of the orphan nuclear receptor Nurr1, interestingly, we identified 6-mercaptopurine as a specific activator of this receptor. A detailed analysis of 6-mercaptopurine regulation of Nurr1 demonstrates that 6-mercaptopurine regulates Nurr1 through a region in the amino terminus. This activity can be inhibited by components of the purine biosynthesis pathway. These findings indicate that Nurr1 may play a role in mediating some of the antiproliferative effects of 6-mercaptopurine and potentially implicate Nurr1 as a molecular target for treatment of leukemias.
authors.affiliation: X-Ceptor Therapeutics, Inc., San Diego, California 92121, USA. pordentlich@x-ceptor.com
authors.forename: Peter
authors.initials: P
authors.lastname: Ordentlich
authors.forename: Yingzhuo
authors.initials: Y
authors.lastname: Yan
authors.forename: Sihong
authors.initials: S
authors.lastname: Zhou
authors.forename: Richard A
authors.initials: RA
authors.lastname: Heyman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000502:physiology; D015122:Mercaptopurine / Q000494:pharmacology*; D008969:Molecular Sequence Data; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D017434:Protein Structure, Tertiary / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000187:drug effects* / Q000502:physiology
chemical_list: D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D015122:Mercaptopurine