Exploring Pharmacological Space
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RESEARCH HIGHLIGHTS INFORMATICS Exploring pharmacological space What can we learn from the data are at a much earlier stage, and how the ligand properties of known integration of vast collections of at present most such data are widely active compounds for protein targets pharmacological data? Can we ration- spread among research papers, patents can be used to derive probabilistic ally expand the search for new drugs and proprietary screening databases. approaches to determining ‘degrees’ of beyond compounds that affect single So, Paolini et al. set out to create a druggability, relative to oral drug space. targets in the ‘druggable genome’? single integrated database, including The analysis also highlights the Insight into key questions such as ~4.8 million compounds and potential for more rational investiga- these has been provided by a recent ~600,000 SARs (for example, IC50 tion of an issue that has attracted extensive analysis, described in Nature values) for ~3,000 protein targets from much interest in drug discovery Biotechnology, which integrates several published and proprietary sources, recently: the notion of polypharma- large sources of structure–activ- with the aim of better understanding cology or ‘dirty drugs’. So far, such ity relationship (SAR) data from ‘pharmacological space’ — the parts drugs, whose therapeutic activity is medicinal chemistry efforts. of chemical space that contain thought to depend on their ability Although databases containing biologically active small molecules. to modulate multiple targets — for protein sequence and structure data In total, the authors identified example, neurotransmitter receptors are well established and widely avail- 529 proteins encoded in the human in the case of several major antipsy- able, analogous resources for SAR genome for which there is at least one chotics — have had a fairly limited compound with a binding affinity amount of rational input in their dis- <100 nM that also satisfies the covery. However, the mapping of poly- Lipinski rule-of-five (the standard pharmacology networks as described criteria for likely oral drug absorp- by Paolini et al. should facilitate the tion). At least one small-molecule development of rational design strate- ‘chemical tool’ (binding affinity <10 gies for selectively promiscuous drugs. μm, but not necessarily satisfying the And overall, increased application rule-of-five) has been identified for of predictive models based on such 836 human proteins. analysis in the assessment of other Several issues that could have important factors in drug discovery considerable significance for future such as druggability and attrition risks drug discovery efforts were also inves- could lead to significant improvement tigated by the authors. For example, in the success rate of the process. they show how a large-scale integrated Peter Kirkpatrick chemogenomics database can be used to build Bayesian models to predict ORIGINAL RESEARCH PAPER Paolini, G. V. et al. compound activity across a virtual Global mapping of pharmacological space. Nature Biotechnol. 24, 805–815 (2006) screening bank of more than 600 FURTHER READING Lipinski, C. & Hopkins, A. protein targets. Furthermore, the Navigating chemical space for biology and authors propose a refinement of medicine. Nature 432, 855–861 (2004) | Hopkins, A. L. & Groom, C. R. The druggable the concept of druggability beyond genome. Nature Rev. Drug Discov. 1, 727–730 (2002) Lipinski’s rule-of-five, by considering RESEARCH HIGHLIGHTS ADVISORS ERIK DE CLERCQ F. PETER GUENGERICH MADS KROGSGAARD THOMSEN CHRISTOPHER LIPINSKI Katholieke Universiteit Leuven, Belgium Vanderbilt University Nashville, TN, USA Novo Nordisk, Bagsvaerd, Denmark Pfizer Global Research and Development, RODERICK FLOWER FRANZ HEFTI HUGO KUBINYI Groton, CT, USA William Harvey Research Institute, QMW, Rinat Neuroscience Corporation, Palo Alto, University of Heidelberg, Germany TOMI SAWYER London, UK CA, USA ROBERT LANGER Massachusetts Institute of Ariad Pharmaceuticals, Cambridge, MA, USA YOSHIJI FUJITA JOAN HELLER BROWN Technology Cambridge, MA, USA JANET WOODCOCK Clinical Proteome Center, Tokyo Medical University of California San Diego, JULIO LICINIO University of California Los Food & Drug Administration, Rockville, University CA, USA Angeles, CA, USA MD, USA NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | SEPTEMBER 2006 | 719 RESEARCH HIGHLIGHTS The idea that endogenous progenitor Encouragingly, such progenitors NEUROLOGICAL DISORDERS cells might be harnessed to replace have been identified in the SNc, and neurons lost in neurodegenerative previous work has demonstrated that diseases is popular, but requires the activation of D3 dopamine receptors New neurons repair development of methods to stimulate stimulates neurogenesis in this region their proliferation and differentia- in healthy adult rats. Parkinson’s brain tion. Hopes for this approach have The new study demonstrates the now received a boost from a study effects of a preferential D3 agonist, by Van Kampen and Eckman, show- 7-OH-DPAT, in a common rat ing that activation of a particular model of Parkinson’s disease, the dopamine receptor subtype stimu- 6-hydroxydopamine model. By label- lates neurogenesis and functional ling cells undergoing DNA synthesis, repair in a Parkinson’s disease model. the researchers showed that chronic Parkinson’s disease involves the drug treatment increased prolifera- degeneration of dopaminergic neu- tion in the SNc. Many new-born cells rons in the nigrostriatal tract, which subsequently expressed proteins projects from the substantia nigra pars typically found in mature dopamin- compacta (SNc) in the midbrain to the ergic neurons. To achieve functional striatum and is essential for the con- recovery and repair of the nigrostriatal trol of movement. Current treatments tract, these newly generated neurons that boost striatal dopamine levels must generate new projections to have adverse side effects, lose efficacy the striatum. This was assessed by over time and do not alter the under- injecting a fluorescent tracer into the lying pathology, making cell-replace- striatum. After retrograde transport ment strategies desirable. Utilizing of the tracer to the SNc, increased endogenous progenitor cells for this numbers of neurons with axons pro- purpose could have advantages over jecting along this tract were revealed. invasive transplantation strategies. Finally, two different behavioural tests prolonged imatinib therapy — IRE1 can KINASE INHIBITORS and dilated endoplasmic reticulum (ER), which are signs of stress. signal cell death by activating the pro- To investigate this further, the authors death JNK pathway. The authors found treated healthy mice with imatinib that JNK was activated in the hearts Stressed out hearts and saw similar structural changes in of imatinib-treated mice and that this the mouse hearts. Doses of imatinib activation was reduced by treatment Imatinib mesylate (Gleevec) potently given to produce blood concentrations with salubrinal, a small-molecule inhibits the kinase activity of the comparable to those in humans led to inhibitor of EIF2α dephosphorylation. oncogenic fusion protein BCR–ABL and These findings left ventricular dysfunction. Imatinib Furthermore, the inhibition of either is an effective treatment for chronic seemed to cause necrotic cell death EIF2α dephosphorylation with myeloid leukaemia. Although imatinib suggest that (as seen by the dose-dependent salubrinal or JNK activity with a peptide seems to be well tolerated by most clinical trials collapse of mitochondrial membrane inhibitor rendered cardiomyocytes patients, more than 60% of patients of new agents potential, release of cytochrome c and resistant to the imatinib-induced on imatinib in clinical trials develop pronounced cytosolic vacuolization) collapse of mitochondrial membrane peripheral oedema, a possible sign of that target rather than apoptosis. Gene transfer potential and cell death. Therefore, the cardiotoxicity. However, heart function ABL should of an imatinib-resistant mutant of ABL imatinib-mediated induction of the ER was not assessed in any of the clinical prospectively inhibited the imatinib-induced release of stress-response pathway leads to cell trials with this agent. Thomas Force and cytochrome c and conferred protection death through the activation of JNKs. colleagues report that 10 patients who assess left against cell death. This suggests that These findings not only suggest that previously had normal heart function ventricular the inhibition of ABL by imatinib is the patients who are on imatinib should developed severe heart failure after the function. mechanism of cardiomyocyte toxicity. be monitored closely for signs of left initiation of imatinib therapy. They found What are the mechanisms ventricular dysfunction, but also that that imatinib is not directly toxic, but that regulate imatinib-induced clinical trials of new agents that target that the inhibition of one of its targets, cardiomyocyte death? Because of ABL should prospectively assess left ABL, triggers the stress response in the observed ER dilation, Force and ventricular function so that rates of cardiomyocytes and induces cell death. colleagues investigated the ER stress- cardiotoxicity can be determined. Myocardial biopsy samples taken from response pathway and found that Ezzie Hutchinson, patients showed prominent membrane imatinib activated both the EIF2α and Nature Reviews Cancer whorls in the myocytes, an abnormality IRE1 parts of this pathway in