Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes

Lower Complexity Bounds for Lifted Inference

One of the big challenges in the development of probabilistic relational (or probabilistic logical) modeling and learning frameworks is the design of inference techniques that operate on the level of the abstract model representation language, rather than on the level of ground, propositional instances of the model. Numerous approaches for such "lifted inference" techniques have been proposed. While it has been demonstrated that these techniques will lead to significantly more efficient inference on some specific models, there are only very recent and still quite restricted results that show the feasibility of lifted inference on certain syntactically defined classes of models. Lower complexity bounds that imply some limitations for the feasibility of lifted inference on more expressive model classes were established early on in (Jaeger 2000). However, it is not immediate that these results also apply to the type of modeling languages that currently receive the most attention, i.e., weighted, quantifier-free formulas. In this paper we extend these earlier results, and show that under the assumption that NETIME =/= ETIME, there is no polynomial lifted inference algorithm for knowledge bases of weighted, quantifier- and function-free formulas. Further strengthening earlier results, this is also shown to hold for approximate inference, and for knowledge bases not containing the equality predicate.Comment: To appear in Theory and Practice of Logic Programming (TPLP

Joyce Apsel on To Plead Our Own Cause: Personal Stories by Today\u27s Slaves. Edited by Kevin Bales and Zoe Trodd (Ithaca, NY: Cornell University Press, 2008). 260pp.

A review of: To Plead Our Own Cause: Personal Stories by Today\u27s Slaves. Edited by Kevin Bales and Zoe Trodd (Ithaca, NY: Cornell University Press, 2008). 260pp

Joyce Apsel on The Oxford Handbook of Genocide Studies. Edited by Donald Bloxham & A. Dirk Moses. New York, NY: Oxford University Press, 2010. 675pp.

A review of: The Oxford Handbook of Genocide Studies. Edited by Donald Bloxham & A. Dirk Moses. New York, NY: Oxford University Press, 2010. 675pp

Noncollinear magnetic ordering in small Chromium Clusters

We investigate noncollinear effects in antiferromagnetically coupled clusters using the general, rotationally invariant form of local spin-density theory. The coupling to the electronic degrees of freedom is treated with relativistic non-local pseudopotentials and the ionic structure is optimized by Monte-Carlo techniques. We find that small chromium clusters (N \le 13) strongly favor noncollinear configurations of their local magnetic moments due to frustration. This effect is associated with a significantly lower total magnetization of the noncollinear ground states, ameliorating the disagreement between Stern-Gerlach measurements and previous collinear calculations for Cr_{12} and Cr_{13}. Our results further suggest that the trend to noncollinear configurations might be a feature common to most antiferromagnetic clusters.Comment: 9 pages, RevTeX plus .eps/.ps figure

Joyce Apsel on Peace: A History of Movements and Ideas. By David Cortright. New York: Cambridge University Press, 2008. 376pp.

A review of: Peace: A History of Movements and Ideas. By David Cortright. New York: Cambridge University Press, 2008. 376pp