Patent Review

The section on patent review will be focused in the areas of interest to the readers of CCHTS. The search was conducted using the following key words: combinatorial chemistry, high throughput screening, drug repurposing, chemical library, high content screening, drug discovery and natural products. All patents highlighted here are identified by the patent number issued either by the World Intellectual Property Organization or by a regional patent office. DRUG REPOSITIONING The paradigm for finding new uses for known or failed drugs has generated new investments and interest in pharmaceutical sector. Drug repositioning or repurposing includes finding different therapeutic indications for drugs with established or even unknown pharmacological mechanism. Both marketed drugs as well as compounds with history of failure during clinical development are candidates for repositioning. Recent patent activity has focused on the experimental methods or theoretical mathematical modeling for selecting drugs for drug repurposing. WO2010141592A2: Chemical fragment screening and assembly utilizing common chemistry for NMR probe introduction and fragment linkage, (Sem, Daniel, S., Marquette University, USA) patent describes a potentially powerful tool to overcome the bottleneck in fragment-based drug design and extends the approach to tailoring known marked drugs for repurposing or increasing potency or reducing side-effects of targeted treatments with existing drugs. The fragment based approach requires identification of short molecular fragments that bind to adjacent sites of a target. One of the fragments, an active scaffold is labeled with 13C-methyl group. The challenges associated with linking two short fragments for drug design is approached using NMR-based fragment assembly. NMR is used at an early stage to detect any transfer of magnetization (NOE) between the labeled scaffold and test fragments, which is detectable only if the fragments bind to a target within 5 Angstrom distance, followed by chemical tethering of the fragments to sites where NOEs were detected. Any substantial increase in the binding affinity of tethered compounds selects the fragments and also precludes the time and cost associated with chemical synthesis of linked fragments. In a related set of patent applications, the uptake of isotope-labeled substrates/precursors in a biological system is accompanied with administration of known or unknown drug (s) or test compound(s). In the patent WO05051434A1: Method for high-throughput screening of compounds and combinations of compounds for discovery and quantification of actions, particularly unanticipated therapeutic or toxic actions, in biological systems (Hellerstein, Marc, K, University of California), the changes in patterns or content of isotopically labeled target molecules is determined in cells, tissues or whole animals through expected or unanticipated metabolic pathways and the rates are compared between labeled systems left untreated with drugs/compounds. An extension of the same principle in related patents WO06017812A1 and WO2007041611A2 focus on quantifying the effect of drugs/compounds on the dynamics of assembly or disassembly of isotopically labeled subunits of cytoskeletal system like the microtubules, amyloid plaques or plasma membrane disruptions. In the following set of patents, methods involving data mining information on diseases, pathways and known drugs forms the basis for the development of various approaches and models to drug repositioning. The patent WO2009068659A2: Novel disease treatment by predicting drug association (Cohen, Daniel; Chumkov, Ilya, Pharnet, France), describes a methodology based on mining of public database to select a disease and build a dynamic model of the disease and the molecular pathways. This is followed by in silico screening of drugs approved for other diseases that encompass all target pathways directly or indirectly implicated in the model. The in silico selected drugs either alone or in combination(s), are then tested in available biological model of the disease, to identify candidates for the treatment of the selected disease. Using this in silico approach, some compounds were proven to have the required biological activity against the targets selected in the patent. The strategy was shown to be effective The patent WO2009027843A2: Techniques for purposing a new compound and for repurposing a drug, (Zoref, Tali, Eilam and Agur, Zvia, Optimata ltd , Israel) describes a computer modeling based approach for repurposing and is based on information and disease models available for an approved drug or for compound(s) that failed in clinical development. Based on information on the drug's pre-clinical and clinical trials, modified pharmacokinetic and pharmacodynamic mathematical models are reconstructed and the model is adjusted based upon information about new patient populations or new indications. A new treatment protocol is suggested to salvage the failed drug or a new way to use an approved drug. HIGH THROUGHPUT SCREENING In patent WO2009078876A1: Assay method for group transfer reactions (Lowery, Robert et al., Bellbrook Labs, LLC, USA), a generic methodology is described for high throughput screening of catalytic activities generating the donor-products in group-transfer reactions of enzymes like methyltransferases, sulfotransferases, kinases, glycosyltransferases, uridine glucuronide transferase, UDP- glucuronosyltransferases, acetyl transferases, glutathione transferases, and ADPribosyltransferases. The methodology is based on generating an antibody which binds with high specificity to the cleaved donor product in a reaction, donor-X + acceptor -» donor-product + acceptor -X. In a methyltransferase reaction, the antibody that specifically binds to S-adenosylhomocysteine with high affinity is used at the detection step in which the enzymatically generated donor product displaces the tracer-labeled donor-product from its complex with the specific antibody, as in fluorescence polarization immunoassay. Because the donor product is the same for all enzymes that catalyze a given type of group transfer reaction, the same detection reagents can be used for all the members within a family of group transfer enzymes and with any acceptor substrate. The assay products can be detected using homogenous fluorescence or chemiluminescence methods.....