Identification of Highly Potent Retinoic Acid Receptor α-Selective Antagonists

Teng, Maikun; Duong, Tien T.; Johnson, A. T. Charlie; Klein, Elliott S.; Wang, Liming; Khalifa, Berket; Chandraratna, Roshantha A.S.

doi:10.1021/jm9703911

Cited by 55 publications

(45 citation statements)

References 26 publications

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“…A stock solution at a concentration of 10 Ϫ3 M was prepared in 95% ethanol, protected from lights with foil, and stored at Ϫ80°C. The RXR agonist AGN194204 and the RAR␣-specific antagonist AGN193109 were provided by Dr. R. Chandraratna of Allergan Inc, Irvine, CA (54 Protein Phosphorylation and Phosphoaminoacid Analysis-Phosphorylation of the AML2 protein and identification of the phosphoamino acids were determined as described in our previous report (65).…”

Section: Methodsmentioning

confidence: 99%

Regulation of AML2/CBFA3 in Hematopoietic Cells through the Retinoic Acid Receptor α-Dependent Signaling Pathway

Le¹,

Groner

Kornblau³

et al. 1999

Journal of Biological Chemistry

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AML2 is a member of the acute myelogenous leukemia, AML family of transcription factors. The biologic functions of AML1 and AML3 have been well characterized; however, the functional role of AML2 remains unknown. In this study, we found that AML2 protein expressed predominantly in cells of hematopoietic origin is a nuclear serine phosphoprotein associated with the nuclear matrix, and its expression is not cell cycle-related. In HL-60 cells AML2 expression can be induced by all three natural retinoids, all-trans-retinoic acid (RA), 13-cis-RA, and 9-cis-RA in a dose-dependent manner. A synthetic retinoic acid derivative, 4HPR, which neither activates RA receptor (RAR) ␣ nor retinoic X receptor ␣ was unable to induce the expression of AML2. A RARselective activator, TTNPB, induced AML2 expression similar to RA. Our study further showed that AGN193109, a potent RAR␣ antagonist, suppressed AML2 expression induced by RA and that a retinoic X receptor pan agonist AGN194204 had no effect on its expression. Taken together, these studies conclusively demonstrated that the expression of AML2 in HL-60 cells is regulated through the RAR␣-specific signaling pathway. Our study further showed that after all-trans-retinoic acid priming, AML2 expression could be augmented by vitamin D 3 . Based on these studies we hypothesize that AML2 expression is normally regulated by retinoid/vitamin D nuclear receptors mainly through the RAR␣-dependent signaling pathway and that it may play a role in hematopoietic cell differentiation.

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Section: Methodsmentioning

confidence: 99%

Regulation of AML2/CBFA3 in Hematopoietic Cells through the Retinoic Acid Receptor α-Dependent Signaling Pathway

Le¹,

Groner

Kornblau³

et al. 1999

Journal of Biological Chemistry

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“…Selectivity can be further increased by incorporating substituents such as halogens on the hydrophobic group as well as by adding fluorine substituents ortho to the carboxylic acid group (e.g., AGN 193836, which was the first monospecific RARa retinoid to be synthesised). [75] In addition, a number of RARa selective inverse agonists, which also contain amide linker groups, but include bulky groups on the hydrophobic unit, have been developed (e.g., AGN 194301 [77] and BMS 614 [24] ), the latter being monospecific. Interestingly, in yeast cells, BMS 614 becomes an RARa specific partial agonist, an effect which has been attributed to the different set of co-activators and co-repressors present in yeast.…”

Section: Rara Selectivitymentioning

confidence: 99%

Synthetic Retinoids: Structure–Activity Relationships

Barnard

Collings

Whiting

et al. 2009

Chemistry A European J

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Retinoid signalling pathways are involved in numerous processes in cells, particularly those mediating differentiation and apoptosis. The endogenous ligands that bind to the retinoid receptors, namely all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid, are prone to double-bond isomerisation and to oxidation by metabolic enzymes, which can have significant and deleterious effects on their activities and selectivities. Many of these problems can be overcome through the use of synthetic retinoids, which are often much more stable, as well as being more active. Modification of their molecular structures can result in retinoids that act as antagonists, rather than agonists, or exhibit a large degree of selectivity for particular retinoid-receptor isotypes. Several such selective retinoids are likely to be of value as pharmaceutical agents with reduced toxicities, particularly in cancer therapy, as reagents for controlling cell differentiation, and as tools for elucidating the precise roles that specific retinoid signalling pathways play within cells.

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“…The synthetic RAR␣-specific agonists AGN194078 20 and AGN195183, 20 the RAR␣-specific antagonist AGN194301, 21 and the pan-RAR antagonist AGN194310 22 were synthesized by Allergan (Irvine, CA).…”

Section: Retinoid Ligandsmentioning

confidence: 99%

Identification of the molecular requirements for an RARα-mediated cell cycle arrest during granulocytic differentiation

Walkley

Purton

Snelling

et al. 2004

Blood

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Retinoids are potent inducers of cell cycle arrest and differentiation of numerous cell types, notably granulocytes. However the mechanisms by which retinoids mediate cell cycle arrest during differentiation remain unclear. We have used myeloid differentiation to characterize the molecular pathways that couple cell cycle withdrawal to terminal differentiation. Using primary cells from mice deficient for either the cyclin-dependent kinase inhibitor (CDKi) p27 Kip1 , the Myc antagonist Mad1, or both Mad1 and p27 Kip1 , we observed that signals mediated through reti- IntroductionThe roles of retinoids during hematopoiesis, particularly granulopoiesis, have been recognized for many years. Most strikingly, retinoids are powerful inducers of differentiation. 1 This effect is central to the use of all-trans-retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL), a leukemia characterized by a chromosomal translocation always involving retinoic acid receptor ␣ (RAR␣). 2,3 Pharmacologic doses of ATRA are able to relieve the repression caused by the fusion proteins via directly binding and activating them and promoting cell cycle arrest and differentiation of the leukemic blasts. 3 However, the mechanisms by which ATRA mediates cell cycle arrest as well as differentiation remain unclear. An understanding of the molecular basis of this effect will provide important insights into how cell cycle withdrawal is coupled to terminal differentiation and how retinoids interact with the cell cycle.The effects of retinoid ligands are mediated through direct binding to the ligand-binding domain of RARs or retinoid X receptors (RXRs), members of the nuclear hormone receptor superfamily. 4 RARs heterodimerize with RXRs, and this heterodimer binds DNA at retinoic acid response elements (RAREs) in the regulatory sequences of target genes. When unliganded, RAR/RXR heterodimers bind RARE and form repressive complexes through binding SMRT-and NCo-R-containing corepressor complexes. 5 Ligand binding triggers the release of the corepressor complexes and coactivator complexes are recruited to the RAR/ RXR dimer and activate gene transcription. [6][7][8] Three isotypes of RARs and RXRs have each been identified: ␣, ␤, and ␥, with each RAR isotype expressed as a number of isoforms. 4 RAR␣ and RAR␥ are believed to be most important in the regulation of granulopoiesis. 4,9 This is most strikingly demonstrated in progenitor assays of bone marrow cells derived from RAR␣1 Ϫ/Ϫ RAR␥ Ϫ/Ϫ mice. These cells displayed a block in granulopoiesis at the myelocyte stage of development, revealing an absolute requirement for RAR-mediated signaling in the terminal differentiation of granulocytes. 9 Our understanding of the mechanisms through which RAR␣ mediates cell cycle arrest and differentiation of myeloid cells is a question of particular relevance. First, RAR␣, but not RAR␤ or RAR␥, is involved in the pathogenesis of myeloid leukemia. 10 RAR␣ is involved in leukemia both as a fusion partner, most commonly involving promyelocytic leukemia...

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Identification of Highly Potent Retinoic Acid Receptor α-Selective Antagonists

Cited by 55 publications

References 26 publications

Regulation of AML2/CBFA3 in Hematopoietic Cells through the Retinoic Acid Receptor α-Dependent Signaling Pathway

Regulation of AML2/CBFA3 in Hematopoietic Cells through the Retinoic Acid Receptor α-Dependent Signaling Pathway

Synthetic Retinoids: Structure–Activity Relationships

Identification of the molecular requirements for an RARα-mediated cell cycle arrest during granulocytic differentiation

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