Adamantyl-Substituted Retinoid-Derived Molecules That Interact with the Orphan Nuclear Receptor Small Heterodimer Partner: Effects of Replacing the 1-Adamantyl or Hydroxyl Group on Inhibition of Cancer Cell Growth, Induction of Cancer Cell Apoptosis, and Inhibition of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase-2 Activity

Abstract

(E)-4-[3-(1-Adamantyl)-4′-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell-cycle arrest and apoptosis of leukemia and cancer cells. Studies demonstrated that 3-Cl-AHPC bound to the atypical orphan nuclear receptor small heterodimer partner (SHP). Although missing a DNA-binding domain, SHP heterodimerizes with the ligand-binding domains of other nuclear receptors to repress their abilities to induce or inhibit gene expression. 3-Cl-AHPC analogues having the 1-adamantyl and phenolic hydroxyl pharmacophoric elements replaced with isosteric groups were designed, synthesized, and evaluated for their inhibition of proliferation and induction of human cancer cell apoptosis. Structure–anticancer activity relationship studies indicated the importance of both groups to apoptotic activity. Docking of 3-Cl-AHPC and its analogues to an SHP computational model that was based on the crystal structure of ultraspiracle complexed with 1-stearoyl-2-palmitoylglycero-3-phosphoethanolamine suggested why these 3-Cl-AHPC groups could influence SHP activity. Inhibitory activity against Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp-2) was also assessed. The most active Shp-2 inhibitor was found to be the 3′-(3,3-dimethylbutynyl) analogue of 3-Cl-AHPC.

Ligand-independent actions of the orphan receptors/corepressors DAX-1 and SHP in metabolism, reproduction and disease

“…In the case of DAX-1 and SHP, there has been much speculation but little progress, perhaps with the notable exception of adamantyl-substituted retinoids binding to SHP [56]. Docking of the compounds CD437/AHPN and MM002/AHPC to a SHP structure model suggested how these compounds could influence SHP activity as true pocket ligands [57]. A potential problem with this method could be that the SHP in silico structural model in this study is based on the X-ray structure of liganded ultraspiracle (USP), which is the Drosophila RXR homologue and only distantly homologues to the SHP LBD.…”

The many faces of the adamantyl group in drug design

“…Substitution of the adamantyl group with a phenyl group in this class of compounds resulted in a 250-fold loss in activity against an ovarian cancer cell line [107]. The ortho disposition of the bulky adamantyl group to the phenolic OH group was also found to be important in activity, in addition to the distance between the adamantyl group and the carboxylic acid [107,110]. Molecular docking experiments between an analogue of 23 and the retinoic acid receptor-g showed an interaction between the adamantyl group and isoleucine and leucine residues [108].…”

Insights into the binding mode and mechanism of action of some atypical retinoids as ligands of the small heterodimer partner (SHP)

“…Very interestingly, this seems to be not an artifact of the crystallization procedure since the same allosteric binding site has been found as functional in other nuclear receptors such as the steroidogenic factor-1 (SF-1) and LHR-1 [42, 43]. In previous works, we already used the 1G2N structure of USP as template to model the structural features of SHP and its interaction with compounds 1 and 2 [22, 32]. …”

“…Thus, the combination of these studies gives rise to an intriguing scenario where small molecules oppositely regulate SHP functions. In line with these observations, further studies by Dawson and coworkers reported the importance of the carboxylic moiety of 1 and 2 for the apoptotic activity and, more recently, an interaction model of these compounds at the proposed ligand binding site of SHP has been suggested, though pending for further experimental appraisals [31, 32]. …”

“…In an attempt to address these issues and in the frame of a research project devoted to the understanding of the molecular basis of ligand binding to SHP [22, 32], we report herein a computational study composed of three parts and supported by mutagenesis experiments. Firstly, a series of homology models of the LBD of SHP endowed with different conformational features, including those of DAX1, is constructed and used to sample the rugged energy landscape of the receptor.…”