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(12) Patent Application Publication (10) Pub. No.: US 2003/0194725A1 Greener Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2003/0194725A1 Greener Et Al US 2003O194725A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0194725A1 Greener et al. (43) Pub. Date: Oct. 16, 2003 (54) METHODS FOR IDENTIFYING AND Publication Classification VALIDATING POTENTIAL DRUG TARGETS (51) Int. Cl." ........................... C12O 1/68; G01N 33/53; (76) Inventors: Tsvika Greener, Ness-Ziona (IL); G06F 19/00; G01N 33/48; Avishai Levy, Rishon-Le-Zion (IL); GO1N 33/50 Yuval Reiss, Kiriat-Ono (IL); Danny (52) U.S. Cl. ................... 435/6; 435/7.1; 702/19; 702/20 Ben-Avraham, Tel-Aviv (IL); Iris Alroy, Ness-Ziona (IL) (57) ABSTRACT Correspondence Address: ROPES & GRAY LLP - X ONE INTERNATIONAL PLACE This application provides methods for identifying and Vali BOSTON, MA 02110-2624 (US) dating potential drug targets. In one aspect, the application provides a Systematic method of creating a database of (21) Appl. No.: 10/299,991 related protein or nucleic acid Sequences with annotations of the potential disease associations of the Sequences, and a (22) Filed: Nov. 19, 2002 method for testing the potential disease associations by Related U.S. Application Data means of a biological assay and validating the disease asSociation by either decreasing expression of the Sequence (60) Provisional application No. 60/331,701, filed on Nov. of interest or increasing expression of the Sequence of 19, 2001. interest. (, OO Download sequence data 102 clean sequence 104 data identify E3 proteins from cleaned 106 sequence data associate disease or biological active with E3 proteins 108 based on their characteristic(s) Patent Application Publication Oct. 16, 2003 Sheet 1 of 5 US 2003/0194725 A1 (, OO re Download sequence data 102 clean sequence data 104 identify E3 proteins from cleaned 106 Sequence data associate disease or biological active with E3 proteins 108 based on their characteristic(s) F.G. 1 Patent Application Publication Oct. 16, 2003 Sheet 2 of 5 US 2003/0194725 A1 o O Sequence data 202 204 E3 Characteristic(s) sequence analysis (e.g., domains and motifs) to 208 E3 ProteinCharacteristic(s) Biological Activity 216 Characteristic Biological Activity 218 220 FIG. 2 Patent Application Publication Oct. 16, 2003 Sheet 3 of 5 US 2003/0194725 A1 | CIVWS 9SeáT?In TOHEIH ZOHEIH JOld333.IgC('IL RIHINV Patent Application Publication Oct. 16, 2003. Sheet 4 of 5 US 2003/0194725 A1 p6wild-type -- p6ATAAP Figure 4 Patent Application Publication Oct. 16, 2003 Sheet 5 of 5 US 2003/0194725 A1 (WT) (Posh-i-WT) P55-> P24-> P24-> Figure 5 US 2003/O194725 A1 Oct. 16, 2003 METHODS FOR DENTIFYING AND VALIDATING protein ligases have previously been identified. See, e.g., POTENTIAL DRUG TARGETS D'Andrea, A. D., et al., Nature Genetics, 18:97 (1998); Gonen, H., et al., Isolation, Characterization, and Purifica RELATED APPLICATIONS tion of a Novel Ubiquitin-Protein Ligase, E3-Targeting of Protein Substrates via Multiple and Distinct Recognition 0001. This application claims the benefit of the filing date Signals and Conjugating Enzymes, J. Biol. Chem., 271:302 of U.S. Provisional Application No. 60/331,701, filed Nov. (1996). Accordingly, E3 enzymes are potential drug targets 19, 2001, the specification of which is hereby incorporated and this application provides a Systematic method for iden by reference in its entirety. tifying and validating potential E3 drug targets. BACKGROUND OF THE INVENTION SUMMARY 0002 Potential drug target validation involves determin 0007. In one aspect, the application provides a systematic ing whether a DNA, RNA or protein molecule is implicated method of creating a database of related protein or nucleic in a disease process and is therefore a Suitable target for acid Sequences with annotations of the potential disease development of new therapeutic drugs. Drug discovery, the asSociations of the Sequences, and a method for testing the proceSS by which bioactive compounds are identified and potential disease associations by means of a biological assay characterized, is a critical Step in the development of new and validating the disease association by either decreasing treatments for human diseases. The landscape of drug dis expression of the Sequence of interest or increasing expres covery has changed dramatically due to the genomics revo Sion of the Sequence of interest. lution. DNA and protein Sequences are yielding a host of new drug targets and an enormous amount of associated 0008. In one aspect, the application provides a method of information. testing and validating potential drug targets. In one aspect the application provides a method of creating a comprehen 0003. The task of deciphering which of these targets are Sive database of related protein and/or nucleic acid implicated in diseases and should be used for Subsequent Sequences, i.e., the protein and nucleic acid Sequences are drug development requires the development of not only included in the database based upon certain Sequence infor Systematic procedures but also high-throughput approaches mation, Structural and/or functional information. In one for determining which targets are a part of disease relevant aspect, the application provides Sequences that are Sorted pathways are critical to the drug discovery process. based upon Sequence, Structural, functional, and biological 0004. The levels of proteins are determined by the bal activity. The Sequences may be further clustered based upon ance between their rates of Synthesis and degradation. The potential disease association; Such as for example, the pres ubiquitin-mediated proteolysis is the major pathway for the ence or absence of certain domains may be indicative of Selective degradation of intracellular proteins. Conse potential disease correlations of that protein or nucleic acid quently, Selective ubiquitination of a variety of intracellular Sequence. The database further comprises annotations indi targets regulates essential cellular functions Such as gene cating the relevant disease correlations. expression, cell cycle, Signal transduction, biogenesis of 0009. The sequences so clustered may be tested for the ribosomes and DNA repair. Another major function of potential associated disease correlations by means of bio ubiquitin ligation is to regulate intracellular protein Sorting. logical assayS. For example, if the associated disease is viral Whereas poly-ubiquitination targets proteins to proteasome infection, a biological assay may be assaying for the release mediated degradation, attachment of a Single ubiquitin mol of Virus like particles, if the disease is a proliferative disease ecule (mono-ubiquitination) to proteins regulates endocyto the biological assay may be determining the rate of prolif sis of cell Surface receptors and Sorting into lysosomes. It eration of the diseased cells. In another aspect, the associ was also demonstrated that ubiquitination controls Sorting of ated disease may be a ubiquitin-mediated disorder and the proteins in the trans-golgi (TGN). assay may determine an aspect of protein degradation, 0005 The linkage of ubiquitin to a substrate protein is protein trafficking, or cellular localization of proteins. In generally carried out by three classes of accessory enzymes other embodiments, the assay may be determining any in a sequential reaction. Ubiquitin activating enzymes (E1) disease characteristic of the associated disease by means of activate ubiquitin by forming a high energy thiol ester the biological assay. intermediate. Activation of the C-terminal Gly of ubiquitin by E1, is followed by the activity of a ubiquitin conjugating 0010. In another aspect, the application provides methods enzyme E2 which Serves as a carrier of the activated thiol of validating the disease associations by decreasing the ester form of ubiquitin during the transfer of ubiquitin expression of the Sequence of interest and determining the directly to the third enzyme, E3 ubiquitin protein ligase. E3 effect of Such a decrease by means of a biological assay. In one embodiment, if the associated disease is a viral infec ubiquitin protein ligase is responsible for the final Step in the tion, the effect of decreasing expression of the Sequence of conjugation proceSS which results in the formation of an interest on the release of the virus like particles is deter isopeptide bond between the activated Gly residue of ubiq mined. Thus, if decreasing the expression of the Sequence of uitin, and an alpha. -NH group of a Lys residue in the interest results in a decrease in the release of the virus like Substrate or a previously conjugated ubiquitin moiety. See, particles the Sequence may be a potential drug target for viral e.g., Hochstrasser, M., Ubiquitin-Dependent Protein Degra infection. Similarly, if decreasing the expression of the dation, Annu. Rev. Genet., 30:405 (1996). Sequence of interest results in a decrease in the rate of 0006 E3 ubiquitin protein ligase, as the final player in the proliferation of a diseased cell Such as a tumor cell the ubiquitination proceSS, is responsible for target Specificity of Sequence may be a potential drug target for proliferative ubiquitin-dependent proteolysis. A number of E3 ubiquitin disorders. Thus, if decreasing the expression alters any US 2003/O194725 A1 Oct. 16, 2003 disease characteristic of the associated disease, the Sequence and determining the differential expression of Said human may be a potential drug target for the associated disease. E3 in a cell exhibiting disease characteristics of an E3 0011. In another embodiment, the application provides asSociated disease and a corresponding
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