BMS 195614 - CAS 253310-42-8
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
BMS 195614 is a neutral RAR α-selective antagonist (Ki = 2.5 nM) and exhibits no significant effect on nuclear receptor corepressor (NCoR) binding. BMS 195614 moderately decreases SMRT binding to RAR and agonist-induced coactivator (CoA) recruitment.
Brife Description:
RARα antagonist
≥98% by HPLC
BMS 195614; BMS195614; BMS-195614; 4-[[[5,6-Dihydro-5,5-dimethyl-8-(3-quinolinyl)-2-naphthalenyl]carbonyl]amino]benzoic acid
Canonical SMILES:
1.A mutation mimicking ligand-induced conformational change yields a constitutive RXR that senses allosteric effects in heterodimers.
Vivat V;Zechel C;Wurtz JM;Bourguet W;Kagechika H;Umemiya H;Shudo K;Moras D;Gronemeyer H;Chambon P EMBO J. 1997 Sep 15;16(18):5697-709.
Mutations of a single residue in the retinoid X receptor alpha (RXRalpha) ligand-binding pocket (LBP) generate constitutive, ligand-binding-competent mutants with structural and functional characteristics similar to those of agonist-bound wild-type RXR. Modelling of the mouse RXRalphaF318A LBP suggests that, like agonist binding, the mutation disrupts a cluster of van der Waals interactions that maintains helix H11 in the apo-receptor location, thereby shifting the thermodynamic equilibrium to the holo form. Heterodimerization with some apo-receptors (retinoic acid, thyroid hormone and vitamin D3 receptors) results in 'silencing' of RXRalphaF318A constitutive activity, which, on the other hand, efficiently contributes to synergistic transactivation within NGFI-B-RXR heterodimers. RAR mutants disabled for corepressor binding and/or lacking a functional AF-2 activation domain, do not relieve RXR 'silencing'. Not only RAR agonists, but also the RAR antagonist BMS614 induce conformational changes allowing RXR to exert constitutive (RXRalphaF318A) or agonist-induced (wild-type RXR) activity in heterodimers. Interestingly, the RXRalphaF318A constitutive activity generated within heterodimers in the presence of BMS614 requires the integrity of both RXR and RAR AF-2 domains.
2.Granulocytic differentiation of human NB4 promyelocytic leukemia cells induced by all-trans retinoic acid metabolites.
Idres N;Benoît G;Flexor MA;Lanotte M;Chabot GG Cancer Res. 2001 Jan 15;61(2):700-5.
The metabolism of all-trans retinoic acid (ATRA) has been reported to be partly responsible for the in vivo resistance to ATRA seen in the treatment of human acute promyelocytic leukemia (APL). However, ATRA metabolism appears to be involved in the growth inhibition of several cancer cell lines in vitro. The purpose of this study was to evaluate the in vitro activity of the principal metabolites of ATRA [4-hydroxy-retinoic acid (4-OH-RA), 18-hydroxy-retinoic acid (18-OH-RA), 4-oxo-retinoic acid (4-oxo-RA), and 5,6-epoxy-retinoic acid (5,6-epoxy-RA)] in NB4, a human promyelocytic leukemia cell line that exhibits the APL diagnostic t(15;17) chromosomal translocation and expresses the PML-RAR alpha fusion protein. We established that the four ATRA metabolites were indeed formed by the NB4 cells in vitro. NB4 cell growth was inhibited (69-78% at 120 h) and cell cycle progression in the G1 phase (82-85% at 120 h) was blocked by ATRA and all of the metabolites at 1 microM concentration. ATRA and its metabolites could induce NB4 cells differentiation with similar activity, as evaluated by cell morphology, by the nitroblue tetrazolium reduction test (82-88% at 120 h) or by the expression of the maturation specific cell surface marker CD11c.
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CAS 253310-42-8 BMS 195614

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