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.
- SourceAvailable from: Jie Wu[Show abstract] [Hide abstract]
ABSTRACT: Protein tyrosine phosphatases (PTPs) are a diverse family of enzymes encoded by 107 genes in the human genome. Together with protein tyrosine kinases (PTKs), PTPs regulate various cellular activities essential for the initiation and maintenance of malignant phenotypes. While PTK inhibitors are now used routinely for cancer treatment, the PTP inhibitor development field is still in the discovery phase. In this article, the suitability of targeting PTPs for novel anticancer drug discovery is discussed. Examples are presented for PTPs that have been targeted for anticancer drug discovery as well as potential new PTP targets for novel anticancer drug discovery.Current pharmaceutical design 03/2010; 16(16):1843-62. DOI:10.2174/138161210791209027 · 3.29 Impact Factor
Conference Paper: Technology for organizational coordination[Show abstract] [Hide abstract]
ABSTRACT: The author discusses integrated simulation models as an organizational coordination mechanism. ENVISION, a software technology, is used to link distributed models, each reflecting the critical aspects and activities of those involved in the collaborative effort. The system views created by model integration formalize the relationships, dependencies, and interactions among the participants and provide a basis for coordinating changes and decisions. Models such as discrete event simulation are developed to capture the concerns and critical variables, parameters, and relationships for each of the members of the collaborative team. ENVISION links the models to create sharable system models that help to formally describe the collaborative task, capture decision streams, and provide a broadly accessible organizational memory for projectsTechnology Management : the New International Language; 11/1991
Conference Paper: Dynamic neural network with heuristics[Show abstract] [Hide abstract]
ABSTRACT: With the deterministic nature and the difficulty of scaling, Hopfield-style neural network is readily to converge to one of local minima in the course of energy function minimization, not to escape from those undesirable solutions. Many researchers, who want to find the global minimum of the traveling salesman problem (TSP), have introduced various approaches to solve such conditions including heuristics, genetic algorithms, hybrid algorithms of some methods, etc. We introduce a simple heuristic algorithm which embeds the classical local search heuristics into the optimization neural network. The proposed algorithm is characterized with the best neighbors selection, which is used in the dynamic scheduling and in ordering the update sequence of neurons, and with the decidability check which is used to guarantee the near-optimal solution. The proposed algorithm enhances both the convergence speed and the quality of solutionsNeural Networks, 1994. IEEE World Congress on Computational Intelligence., 1994 IEEE International Conference on; 01/1994