We report consensus Structure-Activity Similarity (SAS) maps that address the dependence of activity landscapes on molecular representation. As a case study, we characterized the activity landscape of 54 compounds with activities against human cathepsin B (hCatB), human cathepsin L (hCatL), and Trypanosoma brucei cathepsin B (TbCatB). Starting from an initial set of 28 descriptors we selected ten representations that capture different aspects of the chemical structures. These included four 2D (MACCS keys, GpiDAPH3, pairwise, and radial fingerprints) and six 3D (4p and piDAPH4 fingerprints with each including three conformers) representations. Multiple conformers are used for the first time in consensus activity landscape modeling. The results emphasize the feasibility of identifying consensus data points that are consistently formed in different reference spaces generated with several fingerprint models, including multiple 3D conformers. Consensus data points are not meant to eliminate data, disregarding, for example, \"true\" activity cliffs that are not identified by some molecular representations. Instead, consensus models are designed to prioritize the SAR analysis of activity cliffs and other consistent regions in the activity landscape that are captured by several molecular representations. Systematic description of the SARs of two targets give rise to the identification of pairs of compounds located in the same region of the activity landscape of hCatL and TbCatB suggesting similar mechanisms of action for the pairs involved. We also explored the relationship between property similarity and activity similarity and found that property similarities are suitable to characterize SARs. We also introduce the concept of structure-property-activity (SPA) similarity in SAR studies.

Mice with a null mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a disease with marked expansion of granulocytes and macrophages that frequently progresses to a fatal blast crisis, thus resembling human chronic myelogenous leukemia (CML). One important feature of CML is decreased responsiveness of myeloid cells to apoptotic stimuli. Here we show that myeloid cells from mice deficient in ICSBP exhibit reduced spontaneous apoptosis and a significant decrease in sensitivity to apoptosis induced by DNA damage. In contrast, apoptosis in thymocytes from ICSBP-deficient mice is unaffected. We also show that overexpression of ICSBP in the human U937 monocytic cell line enhances the rate of spontaneous apoptosis and the sensitivity to apoptosis induced by etoposide, lipopolysaccharide plus ATP, or rapamycin. Programmed cell death induced by etoposide was specifically blocked by peptides inhibitory for the caspase-1 or caspase-3 subfamilies of caspases. Studies of proapoptotic genes showed that cells overexpressing ICSBP have enhanced expression of caspase-3 precursor protein. In addition, analyses of antiapoptotic genes showed that overexpression of ICSBP results in decreased expression of Bcl-X(L). These data suggest that ICSBP modulates survival of myeloid cells by regulating expression of apoptosis-related genes.