Systems modeling: a pathway to drug discovery

Rajasethupathy, Priyamvada; Vayttaden, Sharat J.; Bhalla, Upinder S.

doi:10.1016/j.cbpa.2005.06.008

Cited by 56 publications

(40 citation statements)

References 47 publications

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“…(Bray, 1995). Investigation of connectivity and the operation logics of these networks is one of the key goals of modern cell biology (Bhalla, 2004;Dueber et al, 2004;Li et al, 2006;Sachs et al, 2002;Sachs et al, 2005) that also has an emerging potential for drug discovery (Rajasethupathy et al, 2005). The aim of the present study was to reveal connectivity of the signaling network mediating the effects of NTFs and laminin on axonal growth and to search for formal rules of signal propagation that would be consistent with experimental data.…”

Section: Resultsmentioning

confidence: 93%

Neurotrophic factors switch between two signaling pathways that trigger axonal growth

Paveliev

Lume

Velthut

et al. 2007

Journal of Cell Science

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There is a major unsolved question in modern cell biology: how does a cell convey environmental information (receptor inputs) into adaptive behavioral programs (motility, gene expression, etc.) (Bray, 1995). A single cell has hundreds of different types of receptor proteins on its surface, making complex combinatorial relationships possible between signaling inputs and signaling network behavior. It remains largely unclear how different combinations of receptor signaling inputs are differentially recognized by the signaling network in such a way as to trigger execution of particular cellular events, such as gene transcription or cytoskeletal rearrangement. Signaling pathways downstream of different receptors are known to crosstalk at many levels and to converge at a limited number of signaling targets. A complex network of signaling pathways mediates the regulatory effects of neurotrophic factors (NTFs) and extracellular matrix (ECM) molecules on a wide spectrum of processes in neurons, including synaptic transmission, axonal growth and posttraumatic regeneration. Many signaling elements of those pathways have been characterized and activatory or inhibitory effects of particular elements on cell function have been described. At the same time, the integral functioning of the signaling network is just beginning to be addressed. It remains largely unclear how distinct pathways are orchestrated in the integrated network to produce highly specific cell responses to receptor stimulation.A critical obstacle to progress in our understanding of cell signaling networks is the lack of a standard unambiguous language allowing quantitative description and analysis of the network behavior (Lazebnik, 2002). The formalism of Boolean algebra was previously used to analyze a genetic network in the specific case of the bacteriophage lambda lysis-lysogeny decision (McAdams and Shapiro, 1995) and it was theoretically predicted that protein kinase signaling networks can be described in Boolean terms (Bhalla, 2003;Bray, 1995;Huang and Ingber, 2000). Moreover, signaling molecules with particular gating behaviors have been generated by means of protein domain recombination (Dueber et al., 2003;Dueber et al., 2004). In the present work, we considered a Boolean network formalism as a framework for experimental design and the interpretation of experimental data on a signaling network behavior.ECM molecules and NTFs are two classes of extracellular ligands that have crucial effects of axonal growth both in vivo and in vitro (Cai et al., 1999;Chen and Strickland, 2003;Ramer et al., 2000). Treatment with NTFs -especially nerve growth factor (NGF) and glial-cell-line-derived neurotrophic factor (GDNF) -is the only known way to induce axonal regeneration into the root entry zone of the spinal cord after dorsal root avulsion (Ramer et al., 2000;Schwab, 2000). GDNF also promotes axonal regeneration in propriospinal neurons after spinal cord injury (Iannotti et al., 2003). Neurturin (NRTN), which is a close homolog of GDNF, restores hindlimb cutan...

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Section: Resultsmentioning

confidence: 93%

Neurotrophic factors switch between two signaling pathways that trigger axonal growth

Paveliev

Lume

Velthut

et al. 2007

Journal of Cell Science

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“…An integrated, pathwayoriented approach that aims at cancer networks in their globality, instead of individual genes in isolation (5), has recently emerged as a potentially attractive alternative to drug discovery (11). However, this may still not be sufficient to capture the complexity of cancer networks, as these pathways are not randomly assembled in tumor cells but compartmentalized in specialized, semiautonomous microenvironments (33).…”

Section: Discussionmentioning

confidence: 99%

“…To overcome these barriers, efforts have begun to explore systems biology tools (10) to model cancer pathways as globally interconnected networks (11). Such connectivity maps, linking together multiple signaling pathways (12), may more faithfully recapitulate the tumor tactics responsible for treatment failure, including redundancy, buffering, and modularity into semiautonomous subnetworks (6).…”

Section: Introductionmentioning

confidence: 99%

“…Such connectivity maps, linking together multiple signaling pathways (12), may more faithfully recapitulate the tumor tactics responsible for treatment failure, including redundancy, buffering, and modularity into semiautonomous subnetworks (6). This information can also be exploited for a novel pathway-oriented drug discovery (11), with the goal of identifying inhibitors of nodal proteins (5), i.e., molecules that integrate multiple signaling subnetworks (6,11). The expectation is that such network inhibitors may be best suited to simultaneously disable multiple mechanisms of tumor maintenance instead of a single gene and thus overcome the genetic and molecular heterogeneity of progressive disease.…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90

Kang

Plescia²,

Song³

et al. 2009

J. Clin. Invest.

209

348

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Although therapeutically targeting a single signaling pathway that drives tumor development and/or progression has been effective for a number of cancers, in many cases this approach has not been successful. Targeting networks of signaling pathways, instead of isolated pathways, may overcome this problem, which is probably due to the extreme heterogeneity of human tumors. However, the possibility that such networks may be spatially arranged in specialized subcellular compartments is not often considered in pathway-oriented drug discovery and may influence the design of new agents. Hsp90 is a chaperone protein that controls the folding of proteins in multiple signaling networks that drive tumor development and progression. Here, we report the synthesis and properties of Gamitrinibs, a class of small molecules designed to selectively target Hsp90 in human tumor mitochondria. Gamitrinibs were shown to accumulate in the mitochondria of human tumor cell lines and to inhibit Hsp90 activity by acting as ATPase antagonists. Unlike Hsp90 antagonists not targeted to mitochondria, Gamitrinibs exhibited a "mitochondriotoxic" mechanism of action, causing rapid tumor cell death and inhibiting the growth of xenografted human tumor cell lines in mice. Importantly, Gamitrinibs were not toxic to normal cells or tissues and did not affect Hsp90 homeostasis in cellular compartments other than mitochondria. Therefore, combinatorial drug design, whereby inhibitors of signaling networks are targeted to specific subcellular compartments, may generate effective anticancer drugs with novel mechanisms of action.

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“…Armed with a good understanding of the disease from the regulatory network level, the company used model predictions to develop a fully humanized anti-Factor IX antibody that has entered clinical trials. Rajasethupathy et al have recently reviewed advances in the practical applications of systems biology to drug discovery [20]. These researchers promote the development of network-based drug design, which devises drug-treatment strategies from the level of the disease system using computational models and highthroughput experiments.…”

Section: Introductionmentioning

confidence: 99%

Dynamic simulations on the Arachidonic Acid Metabolic Network

Yang¹,

Ma²,

Liang³

et al. 2005

PLoS Comput Biol

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Drug molecules not only interact with specific targets, but also alter the state and function of the associated biological network. How to design drugs and evaluate their functions at the systems level becomes a key issue in highly efficient and low-side-effect drug design. The arachidonic acid metabolic network is the network that produces inflammatory mediators, in which several enzymes, including cyclooxygenase-2 (COX-2), have been used as targets for antiinflammatory drugs. However, neither the century-old nonsteriodal anti-inflammatory drugs nor the recently revocatory Vioxx have provided completely successful anti-inflammatory treatment. To gain more insights into the anti-inflammatory drug design, the authors have studied the dynamic properties of arachidonic acid (AA) metabolic network in human polymorphous leukocytes. Metabolic flux, exogenous AA effects, and drug efficacy have been analyzed using ordinary differential equations. The flux balance in the AA network was found to be important for efficient and safe drug design. When only the 5-lipoxygenase (5-LOX) inhibitor was used, the flux of the COX-2 pathway was increased significantly, showing that a single functional inhibitor cannot effectively control the production of inflammatory mediators. When both COX-2 and 5-LOX were blocked, the production of inflammatory mediators could be completely shut off. The authors have also investigated the differences between a dual-functional COX-2 and 5-LOX inhibitor and a mixture of these two types of inhibitors. Their work provides an example for the integration of systems biology and drug discovery.

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Systems modeling: a pathway to drug discovery

Cited by 56 publications

References 47 publications

Neurotrophic factors switch between two signaling pathways that trigger axonal growth

Neurotrophic factors switch between two signaling pathways that trigger axonal growth

Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90

Dynamic simulations on the Arachidonic Acid Metabolic Network

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