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(12) Patent Application Publication (10) Pub. No.: US 2010/0304998 A1 Sem (43) Pub US 20100304998A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0304998 A1 Sem (43) Pub. Date: Dec. 2, 2010 (54) CHEMICAL PROTEOMIC ASSAY FOR Related U.S. Application Data OPTIMIZING DRUG BINDING TO TARGET (60) Provisional application No. 61/217,585, filed on Jun. PROTEINS 2, 2009. (75) Inventor: Daniel S. Sem, New Berlin, WI Publication Classification (US) (51) Int. C. GOIN 33/545 (2006.01) Correspondence Address: GOIN 27/26 (2006.01) ANDRUS, SCEALES, STARKE & SAWALL, LLP C40B 30/04 (2006.01) 100 EAST WISCONSINAVENUE, SUITE 1100 (52) U.S. Cl. ............... 506/9: 436/531; 204/456; 435/7.1 MILWAUKEE, WI 53202 (US) (57) ABSTRACT (73) Assignee: MARQUETTE UNIVERSITY, Disclosed herein are methods related to drug development. Milwaukee, WI (US) The methods typically include steps whereby an existing drug is modified to obtain a derivative form or whereby an analog (21) Appl. No.: 12/792,398 of an existing drug is identified in order to obtain a new therapeutic agent that preferably has a higher efficacy and (22) Filed: Jun. 2, 2010 fewer side effects than the existing drug. Patent Application Publication Dec. 2, 2010 Sheet 1 of 22 US 2010/0304998 A1 augavpop, Patent Application Publication Dec. 2, 2010 Sheet 2 of 22 US 2010/0304998 A1 g Patent Application Publication Dec. 2, 2010 Sheet 3 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 4 of 22 US 2010/0304998 A1 tg & Patent Application Publication Dec. 2, 2010 Sheet 5 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 6 of 22 US 2010/0304998 A1 s Patent Application Publication Dec. 2, 2010 Sheet 7 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 8 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 9 of 22 US 2010/0304998 A1 s Patent Application Publication Dec. 2, 2010 Sheet 10 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 11 of 22 US 2010/0304998 A1 : 8& & S S 8 S & N Patent Application Publication Dec. 2, 2010 Sheet 12 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 13 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 14 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 15 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 16 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 17 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 18 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 19 of 22 US 2010/0304998 A1 **************************************************^*^®^^^*^®^^^*^®^^^*^- laenol wur.6) ??????. wunog ?umizu Patent Application Publication Dec. 2, 2010 Sheet 20 of 22 US 2010/0304998 A1 g Patent Application Publication Dec. 2, 2010 Sheet 21 of 22 US 2010/0304998 A1 Patent Application Publication Dec. 2, 2010 Sheet 22 of 22 US 2010/0304998 A1 Papwaissapixiisweswuri, US 2010/0304998 A1 Dec. 2, 2010 CHEMICAL PROTEOMIC ASSAY FOR preferably has an affinity for the non-target protein that is less OPTIMIZING DRUG BINDING TO TARGET than the affinity of the existing drug for the target protein. PROTEINS 0007. In some embodiments, the methods include the fol lowing steps: (a) passing a biological sample comprising a CROSS-REFERENCE TO RELATED target protein and optionally a non-target protein over a col APPLICATIONS umn, the column comprising an affinity resin for the target protein, the affinity resin comprising a resin conjugated or 0001. The present application claims the benefit under 35 covalently attached to a first chemical compound that binds to U.S.C. S 119(e) to U.S. Provisional Application No. 60/217, the target protein; (b) washing the column and removing 585, filed on Jun. 2, 2009, the contents of which are incorpo proteins that are not bound to the affinity resin; (c) eluting rated herein by reference. proteins from the column that are bound to the affinity resin BACKGROUND by passing a solution comprising a second chemical com pound over the column; and (d) identifying proteins in the 0002 The field of the present invention relates to drug eluate and optionally obtaining a proteomic profile for the development. In particular, the invention relates to methods second chemical compound. Optionally, the methods further for modifying or repurposing existing drugs to obtain a new may include: (e) comparing the identified proteins of the therapeutic having higher efficacy and fewer side effects. eluate obtained using the second chemical compound to iden 0003. The drug discovery process is costly and often inef tified proteins of an eluate obtained using the first chemical ficient. Genomics and proteomics advances have presented compound (e.g., comparing the proteomic profile of the sec the promise of improving efficiency, but this has largely trans ond chemical compound to the proteomic profile of the first lated into the identification of new drug targets, not new chemical compound. drugs. What is needed is a better coupling of the chemistry of 0008. The first and second chemical compounds utilized drug design to advances in genomics and proteomics. in the method may be related or unrelated. In some embodi 0004 Drugs typically exert their desired therapeutic ments, the second chemical compound is a derivative orana effects and their undesired side effects by virtue of binding log of the first chemical compound and binds to the target interactions with protein target(s) and anti-target(s), respec protein. In other embodiments, the first chemical compound tively. Better strategies are therefore needed to efficiently and the second chemical compound are selected from Table monitor and manipulate cross-target binding profiles (i.e. the 6-9, and optionally, the second chemical compound binds to collection of proteins that a drug molecule binds to), as an the target protein. integrated part of the drug design process. Notably, it was 0009. In some embodiments of the disclosed methods, the only recently discovered that two widely-used drugs, ima first chemical compound is an existing drug for which a target tinib and isoniazid, actually bind to multiple proteins. This protein has been identified in the art and the second chemical was only discovered years after these drugs were in use. It compound is a derivative or analog of the existing drug which should also be noted that drug binding to other proteins, while binds to the target protein. In the methods, the biological Sometimes leading to toxic side-effects, can in some cases, sample includes the target protein. Typically, the biological such as imatinib (4-(4-Methyl-1-piperazinyl)methyl-N-(4- sample is obtained from a physiologically relevant tissue with methyl-3-4-(3-pyridinyl)-2-pyrimidinyl)amino-phenyl respect to the therapeutic target of the existing drug. For benzamide methanesulfonate) and isoniazid, actually con example, where the existing drug is utilized as a neurological tribute to drug efficacy, thereby calling into question the one therapeutic and is known to have a target protein that is target/one-drug dogma that has long served as the foundation present in neural tissue, the biological sample for the present for rational drug design. methods may be obtained from neural tissue. Where an exist 0005. The methods disclosed herein may be utilized to ing drug is observed to cause side effects due to toxicity, the define proteomic profiles early in the drug discovery process. existing drug may be observed to bind to a non-target protein As such, lead drugs may be modified in order to tune or adjust which may be present in physiologically non-relevant tissue these proteomic profiles. The methods disclosed herein also with respect to the therapeutic target of the existing drug (e.g., may be utilized to assay for off-target binding events, for non-neural tissue Such as liver tissue or heart tissue for exist example, so that multi-target binding can be better correlated ing drugs utilized as neurological therapeutics), and which with desired therapeutic effects. optionally may be present in physiologically relevant tissue with respect to the therapeutic target of the existing drug (e.g., SUMMARY neural tissue for existing drugs utilized as neurological thera 0006 Disclosed herein are methods related to drug devel peutics). opment. The methods typically include steps whereby an 0010. In the disclosed methods, the proteins of the biologi existing drug is modified to obtain a derivative form or cal sample are bound to the column containing the affinity whereby an analog of an existing drug is identified in order to resin and Subsequently the proteins are eluted. For example, obtain a new therapeutic agent which preferably has a higher the proteins bound to the column may be eluted by washing efficacy and fewer side effects than the existing drug. In some the column with a solution comprising the first chemical embodiments, the existing drug is utilized as an affinity agent compound (e.g., an existing drug) or a derivative or analog in order to identify proteins in a biological sample that bind to thereof, where the affinity resin of the first column is made of the existing drug, including a target protein and optionally a a resin conjugated or covalently attached to the first chemical non-target protein. A derivative or analog of the existing drug compound. then is tested in order to determine: (1) whether the derivative 0011. In the disclosed methods, the proteins in the eluates or analog preferably has an affinity for the target protein that typically are identified, for example, in order to obtain a is no less than the affinity of the existing drug for the target proteomic profile.
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