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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

What Are Next Generation Innovative Therapeutic Targets? Clues from Genetic, Structural, Physicochemical, and Systems Profiles of Successful Targets

Feng Zhu, LianYi Han, ChanJuan Zheng, Bin Xie, Martti T. Tammi, ShengYong Yang, YuQuan Wei and YuZong Chen
Journal of Pharmacology and Experimental Therapeutics July 2009, 330 (1) 304-315; DOI: https://doi.org/10.1124/jpet.108.149955
Feng Zhu
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LianYi Han
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ChanJuan Zheng
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Bin Xie
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Martti T. Tammi
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ShengYong Yang
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YuQuan Wei
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YuZong Chen
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Abstract

Low target discovery rate has been linked to inadequate consideration of multiple factors that collectively contribute to druggability. These factors include sequence, structural, physicochemical, and systems profiles. Methods individually exploring each of these profiles for target identification have been developed, but they have not been collectively used. We evaluated the collective capability of these methods in identifying promising targets from 1019 research targets based on the multiple profiles of up to 348 successful targets. The collective method combining at least three profiles identified 50, 25, 10, and 4% of the 30, 84, 41, and 864 phase III, II, I, and nonclinical trial targets as promising, including eight to nine targets of positive phase III results. This method dropped 89% of the 19 discontinued clinical trial targets and 97% of the 65 targets failed in high-throughput screening or knockout studies. Collective consideration of multiple profiles demonstrated promising potential in identifying innovative targets.

Footnotes

  • This work was supported by the Academic Research Funds Singapore [Grant R-148-000-081-112]; the National Natural Science Foundation of China [Grant 30772651]; and the Ministry of Science and Technology, 863 Hi-Tech Program China [Grant 2006AA020400].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.149955.

  • ABBREVIATIONS: HTS, high-throughput screening; BLAST, Basic Local Alignment Search Tool; SVM, support vector machine(s); NK, neurokinin; MMP, matrix metalloproteinase; PI-88, phosphomannopentaose sulfate; AMD-3100, 1,1′-[1,4-phenylenebis(methylene)]bis [1,4,8,11-tetraazacyclotetradecane] octohydrobromide dihydrate; PXD101, belinostat; SNS-032, N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; UCN-01, 7-hydroxystaurosporine; HMN-214, (E)-4-(2-(2-(N-acetyl-N-(4-methoxybenzenesulfonyl)amino)stilbazole)) 1-oxide; AT7519, 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide; SNS-032, N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; TAK-475, 1-((1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)acetyl)piperidine-4-acetic acid; R115777, tipifarnib; IPI-504, 17-(allylamino)-17-demethoxygeldanamycin; LY335979, zosuquidar trihydrochloride; CGP71683A, N-[[4-[[(4-aminoquinazolin-2-yl)amino]methyl]cyclohexyl]methyl]naphthalene-1-sulfonamide; ABT-239, 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile; LY293111, 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-propoxy]phenoxyl]benzoic acid; LY2140023, (1R,4S,5S,6S)-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid, 4-[(2S)-2-amino-4-(methylthio)-1-oxobutyl]amino-, 2,2-dioxide monohydrate; LY354740, (2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-dioic acid; NSCLC, non–small-cell lung carcinoma; BMS-275291, (S)-N-[2-mercapto-1-oxo-4-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)butyl]-l-leucyl-N,3-dimethyl-l-valinamide; SCH-530348, (9-{2-[5-(3-fluorophenyl)-pyridin-2-yl]-vinyl}-1-methyl-3-oxo-dodecahydro-naphtho[2,3-c]furan-6-yl)-carbamic acid ethyl ester; AMD-070, N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine; DX-88, ecallantide; CI-1033, N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide; XL999, 5-(1-ethyl-piperidin-4-ylamino)-3-[(3-fluorophenyl)-(4-methyl-1H-imidazol-2-yl)-methylene]-1,3-dihydro-indol-2-one; CHIR-258, 4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one; MS-275, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)aminomethyl]benzamide; KD3010, 4-[2,6-dimethyl-4-(4-trifluoromethoxyphenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid; RX-0201, 5′-GCTGCATGATCTCCTTGGCG-3′; DG031, 2-(4-(quinolin-2-yl-methoxy)-phenyl)-2-cyclopentylacetic acid; CNF1010, carbamic acid 19-allylamino-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-aza-bicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl ester; SNX-5422, amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester; PG-530742, 2-[4-(4-methoxy-benzoylamino)-benzenesulfonylamino]-6-morpholin-4-ylhex-4-ynoic acid; GD0039, octahydro-indolizine-1,2,8-triol; BB-3644, N1-[2,2-dimethyl-1-(pyridin-2-ylcarbamoyl)-propyl]-N4-hydroxy-2-isobutyl-3-methoxy-succinamide; AZD 7545, (2R)-N-{4-[4-(dimethylcarbamoyl)phenylsulfonyl]-2-chlorophenyl}-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide; CAP-232, (1R,4S,7R,10S,13R)-4-(4-aminobutyl)-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]-13-[[(2R)-2-amino-3-phenylpropanoyl]amino]-10-[(4-hydroxyphenyl)methyl]-7-(1H-indol-3-ylmethyl)-3,6,9,12-tetraoxo-15,16-dithia-2,5,8,11-tetrazacycloheptadecane-1-carboxamide; C1-INH,MASRLTLLTLLLLLLAGDRASSNPNATSSS-SQDPESLQDRGEGKVATTVISKMLFVEPILEVSSLPTTNSTTNSATKITANTTDEPTTQPTTEPTTQPTIQPTQPTTQLPTDSPTQPTTGSFCPGPVTLCSDLESHSTEAVLGDALVDFSLKLYHAFSAMKKVETNMAFSPFSIASLLTQVLLGAGENTKTNLESILSYPKDFTCVHQALKGFTTKGVTSVSQIFHSPDLAIRDTFVNASRTLYSSSPRVLSNNSDANLELINTWVAKNTNNKISRLLDSLPSDTRLVLLNAIYLSAKWKTTFDPKKTRMEPFHFKNSVIKVPMMNSKKYPVAHFIDQTLKAKVGQLQLSHNLSLVILVPQNLKHRLEDMEQALSPSVFKAIMEKLEMSKFQPTLLTLPRIKVTTSQDMLSIMEKLEFFDFSYDLNLCGLTEDPDLQVSAMQHQTVLELTETGVEAAAASAISVARTLLVFEVQQPFLFVLWDQQHKFPVFMGRVYDPRA; INCB3284, 1-hydroxy-4-[3-isopropyl-3-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridine-6-carbonyl)-cyclopentylamino]-cyclohexanecarbonitrile; TM30339, APLEPVYPGDNATPEQMAQYAADLRRYINMLTRPRY; KAI-9803, H2N-Cys-Ser-Phe-Asn-Ser-Tyr-Glu-Leu-Gly-Ser-Leu-COOH; XL647, (3,4-dichloro-phenyl)-{6-methoxy-7-[5-(4-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy]-quinazolin-4-yl}-amine; KOS-2187, 7,10,12,13-tetrahydroxy-6-[3-hydroxy-4-(isopropyl-methyl-amino)-6-methyl-tetrahydro-pyran-2-yloxy]-4-(5-hydroxy-4-methoxy-4,6-dimethyl-tetrahydro-pyran-2-yloxy)-3,5,7,9,11,13-hexamethyl-14-phenyl-oxacyclotetradecan-2-one; CPG 52364, N′-[6,7-dimethoxy-2-(4-phenyl-piperazin-1-yl)-quinazolin-4-yl]-N,N-dimethyl-ethane-1,2-diamine; REG1, a two-component system consisting of a single-stranded nucleic acid aptamer RB006 3′-idT-UACCCCUCCGUCCUAAUGCGCCAUAUCAGGGGUA-Ch-5′ and a complementary antidote nucleic acid RB007 3′-uaccccugauauggcgc-5′; MBX-8025, formerly RWJ-800025, {2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-phenoxy}-acetic acid; XL844, 1-[2-(3-amino-propoxy)-phenyl]-3-pyrazin-2-yl-urea; XL880, cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-amide (4-fluoro-phenyl)-amide; AM803, [3-hydroxy-2-methylsulfanylmethyl-5-(pyridin-2-ylmethoxy)-pyrrolo[2,3-b]pyridin-1-yl]-acetaldehyde; AM103, 2-[2-(2-oxo-propyl)-5-(quinolin-2-ylmethoxy)-pyrrolo[2,3-b]pyridin-1-yl]-acetamide; 659032, 2-[[(2,3-difluorophenyl)methyl]thio]-N-[1-(2-methoxyethyl)-4-piperidinyl]-4-oxo-N-[[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]methyl]-1(4H)-quinolineacetamide; AE-941, an analog of squalamine 3β-N-1-[N-[3-(4-aminobutyl)]-1,3-diaminopropane]-7-α-cholestane 24-sulfate; PSN357, 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-1-(4-fluoro-benzyl)-2-oxo-ethyl]-amide; RC-8800, 5-(2-{1-[3-(3,4-dichloro-benzenesulfonyl)-1-methyl-propyl]-7α-methyl-octahydro-inden-4-ylidene}-ethylidene)-4-methylene-cyclohexane-1,3-diol; MLN222, CEEPPTFEAMELIGKPKPYYEIGERVDYKCKKGYFYIPPLATHTICDRNHTWLPVSDDACYRETCPYIRDPLNGQAVPANGTYEFGYQMHFICNEGYYLIGEEILYCELKGSVAIWSGKPPICEKVLCTPPPKIKNGKHTFSEVEVFEYLDAVTYSCDPAPGPDPFSLIGESTIYCGDNSVWSRAAPECKVVKCRFPVVENGKQISGFGKKFYYKATVMFMTVARPSVPAALPLLGELPRLLLLVLLCLPAVWGDCGLPPDVPNAQPALEGRTSFPEDTVITYKCEESFVKIPGEKDSVICLKGSQWSDIEEFCNRSCEVPTRLNSASLKQPYITQNYFPVGTVVEYECRPGY-RREPSLSPKLTCLQNLKWSTAVEFCKKKSCPNPGEIRNGQIDVPGGILFGATISFSCNTGYKLFGSTSSFCLISGSSVQWSDPLPECREIYCPAPPQIDN-GIIQGERDHYGYRQSVTYACNKGFTMIGEHSIYCTVNNDEGEWSGPPPECRGKSLTSKVPPTVQKPTTVNVPTTEVSPTSQKTTTKTTTP; XL418, 3-bromo-4-{4-[5-chloro-2-methyl-3-(3-pyrrolidin-1-yl-propyl)-phenyl]-piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine.

  • ↵ Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • Received December 16, 2008.
  • Accepted April 7, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

What Are Next Generation Innovative Therapeutic Targets? Clues from Genetic, Structural, Physicochemical, and Systems Profiles of Successful Targets

Feng Zhu, LianYi Han, ChanJuan Zheng, Bin Xie, Martti T. Tammi, ShengYong Yang, YuQuan Wei and YuZong Chen
Journal of Pharmacology and Experimental Therapeutics July 1, 2009, 330 (1) 304-315; DOI: https://doi.org/10.1124/jpet.108.149955

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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

What Are Next Generation Innovative Therapeutic Targets? Clues from Genetic, Structural, Physicochemical, and Systems Profiles of Successful Targets

Feng Zhu, LianYi Han, ChanJuan Zheng, Bin Xie, Martti T. Tammi, ShengYong Yang, YuQuan Wei and YuZong Chen
Journal of Pharmacology and Experimental Therapeutics July 1, 2009, 330 (1) 304-315; DOI: https://doi.org/10.1124/jpet.108.149955
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