Harnessing network biology to improve drug discovery

Medicilon has been recognized as one of the top drug discovery contract research organizations (CRO) in China and is managed by a team of scientists with a wealth of experience in US-based pharmaceutical and biotechnology companies. As our areas of expertise and service capabilities continue to expand, more and more pharmaceutical and biotechnology companies have taken advantage of our integrated drug discovery and development services. email:marketing@medicilon.com.cn web:www.medicilon.com

ABSTRACT:This invention provides principles, methods and compositions for ascertaining the mechanism of action of pharmacologically important compounds in the context of network biology, across the entire scope of the complex pathways of living cells. Importantly, the principles, methods and compositions provided allow a rapid assessment of the on-pathway and off-pathway effects of lead compounds and drug candidates in living cells, and comparisons of lead compounds with well-characterized drugs and toxicants to identify patterns associated with efficacy and toxicity. The invention will be useful in improving the drug discovery process, in particular by identifying drug leads with desired safety and efficacy and in effecting early attrition of compounds with potential adverse effects in man.

BACKGROUND OF THE INVENTION:The central challenge of the pharmaceutical industry is to develop drugs that are both safe and effective in man. Even an exquisitely selective chemical compound that binds to a therapeutic target may have completely unexpected or 'off-pathway' effects in living cells, leading to expensive pre-clinical and clinical failures. Regardless of whether a drug or drug candidate is an agonist, antagonist, inhibitor or activator of a target, drugs exert their actions by binding to a target protein and altering the function of that protein. For the purposes of this invention, we define 'off pathway' activity as any activity of a compound on a cellular target or pathway other than the intended target of the compound. As evidenced by the 75% failure rate of drugs in clinical trials, the development of new drugs is a costly and unpredictable process, despite the number of research tools available to the pharmaceutical industry. The US Food and Drug Administration has estimated that even a 10% improvement in identifying adverse effects of compounds, prior to clinical trials, could save $100 Million in drug development costs per drug (reference white paper). Our central premise is that the off-pathway effects of new drugs are responsible for many if not all of the failures in new drug development. An understanding of the full spectrum of biological activity of any new chemical entity would help to identify potentially adverse effects of drugs prior to clinical trials. Therefore, we sought to establish a rapid method to assess the activity of any new chemical entity in the context of the complex networks of living cells.

Numerous in vivo and in vitro approaches are aimed at assessing the selectivity of lead compounds. Typical methods are briefly described here.

The selectivity of a compound can be assessed by constructing panels of in vitro assays to measure the activity of the compound against individual proteins in the target class. An example is the target class comprised of protein (tyrosine and serine/threonine) kinases. There are over 500 distinct protein kinases in the mammalian genome, making the development of selective inhibitors particularly challenging. A variety of companies (e.g. PanLabs, Kinexus) have established kinase inhibitor profiling products and services designed to assess the selectivity of lead compounds by testing each compound in vitro against panels of individual, purified kinases. The completion of the mapping of the 'kinome' and the availability of full-length genes encoding human kinases has aided in the development of such assay panels. Although such assay panels exist for kinases, as well as for many other common drug target classes such as G-protein-coupled receptors (GPCRs), such panels are only capable of assessing drug activity against the proteins that are directly assayed. Even if it were possible to construct an assay for every kinase in the kinome, the approach would be limited in its ability to identify off-pathway effects of kinase leads. The most significant limitation is that even a highly selective inhibitor of a kinase may be capable of binding, activating, or inhibiting a plethora of other proteins that are not even in the same target class. Such off-target/off-pathway activities are unpredictable, and cannot be assessed in a comprehensive way with in vitro assays. Since the number of proteins in the proteome exceeds 30,000, a comprehensive analysis would require testing every compound of interest against over 30,000 proteins. First, it would be necessary to purify each of the thousands of proteins in the human proteome; and then to construct a biochemical assay to measure the activity of that particular protein; and finally, to assay each chemical compound of interest in 30,000 discrete assays. This is not practical or even feasible in the near future.