Wrapping technology and the enhancement of specificity in cancer drug treatment.

Molecularly targeted treatment of malignancy requires a careful control of drug specificity. We review recent advances in this area focusing on a particular marker for ligand-target associations: the poorly wrapped hydrogen bond or dehydron, a packing defect in the protein target. Dehydrons promote their own dehydration and are generally not conserved across homologs. Thus, the so-called "wrapping technology" is geared at enhancing drug specificity by developing ligands that can contribute exogenously to shield dehydrons from water attack. This type of design is guided by an analysis of protein interfaces and the assessment of environmental changes around preformed hydrogen bonds occurring upon association. Dehydron differences across a-priori targets have been exploited to redesign drugs in order to enhance selectivity. Tested wrapping modifications to established cancer drugs are reviewed. The rationally directed impact of the prototype compounds points to a broad applicability of the wrapping technology, ultimately leading to molecular therapies with tighter control of side effects. New perspectives on the treatment of cancer progression using the wrapping technology are outlined. In particular, we discuss a future strategy to develop highly selective inhibitors targeting a signaling complex critical to cancer metastasis.