ORGN 3 |
| Nature has exploited phosphorus in many novel ways ranging from structural composition of membrane lipid bilayers to nucleic acids and a plethora of intracellular proteins which are integral to signal transduction by virtue of phosphorylation at key amino acids. Protein kinases and protein phosphatases modulate the phosphorylation states of signal transduction proteins and their catalytic, adapter or other functional properties that are critical to cellular mechanisms involving metabolism, differentiation, proliferation, survival and motility. The phosphorus moiety in such cases exists chemically as a phosphate ester, a rather simple and yet multifunctional moiety for biological activity. Drug discovery efforts have mostly been focused on mimicking the phosphate moiety by bioisosteres, including phosphonates, phosphinates, and non-phosphorus groups (e.g., carboxylic acids). Pyrophosphate analogs modified at the ester oxygen atom by replacement with di-substituted carbon have emerged as breakthrough medicines relative to their unique properties for bone-targeting and biological activities for bone diseases (e.g, osteoporosis and bone metastasis). Relative to exploiting a more extensive scope of the chemical, biological and 3D-structural properties of phosphorus-containing functional groups, we advanced several series of novel peptidomimetic, nonpeptide, amino acid, and small-molecule ligands for varying therapeutic targets involved in signal transduction pathways. Specific examples include inhibitors of oncogenic protein kinases incorporating mono- or bis-phosphorus groups and expanding the chemotypes to phosphine oxides will be illustrated. A technology platform dubbed SMART Drug Design that exploits phosphorus in the generation, optimization and development of both proof-of-concept ligands and breakthrough medicines will be discussed within the context of signal transduction modulation for cancer therapy. |
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Ralph F. Hirschmann Award in Peptide Chemistry
8:00 AM-12:00 PM, Sunday, 13 March 2005 Convention Center -- Ballroom 20A-B, Oral
Division of Organic Chemistry |