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

Cancer Center and Inflammatory and Infectious Disease Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 09/2008; 51(18):5650-62. DOI: 10.1021/jm800456k
Source: PubMed


(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.

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