Q1 · MEDICINE
Article
Author: Zhang, Xiao-Kun ; Hobbs, Peter D. ; Xue, Li Ping ; Farhana, Lulu ; Ye, Mao ; Nuti, Roberto ; Jiang, Tao ; Dawson, Marcia I. ; Xia, Zebin ; Pellicciari, Roberto ; Jong, Ling ; Chao, Wan-ru ; Macchiarulo, Antonio ; Han, Young-Hoon ; Su, Ying ; Bhuiyan, Mohammad ; Patel, Bhaumik ; Waleh, Nahid ; Pang, Yuhong ; Fontana, Joseph A. ; Feng, Gen-Sheng ; Tautz, Lutz
(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.