Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells

J Med Chem. 1995 Aug 4;38(16):3146-55. doi: 10.1021/jm00016a018.


Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.

MeSH terms

  • Apoptosis / drug effects*
  • Bexarotene
  • Binding, Competitive
  • Cell Line
  • Drug Design
  • Humans
  • Leukemia, Promyelocytic, Acute
  • Ligands
  • Niacin / analogs & derivatives
  • Niacin / metabolism
  • Nicotinic Acids / chemistry
  • Nicotinic Acids / metabolism
  • Nicotinic Acids / pharmacology
  • Receptors, Retinoic Acid / metabolism*
  • Retinoid X Receptors
  • Retinoids / chemical synthesis
  • Retinoids / metabolism
  • Retinoids / pharmacology*
  • Structure-Activity Relationship
  • Tetrahydronaphthalenes / chemical synthesis
  • Tetrahydronaphthalenes / chemistry
  • Tetrahydronaphthalenes / metabolism
  • Tetrahydronaphthalenes / pharmacology
  • Transcription Factors / metabolism*
  • Transglutaminases / metabolism
  • Tumor Cells, Cultured


  • Ligands
  • Nicotinic Acids
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Retinoids
  • Tetrahydronaphthalenes
  • Transcription Factors
  • Niacin
  • Bexarotene
  • Transglutaminases
  • LG 100268