Discovery of a Potent Small Molecule IL-2 Inhibitor through Fragment Assembly
Using a site-directed fragment discovery method called tethering, we have identified a 60 nM small molecule antagonist of a cytokine/receptor interaction (IL-2/IL2Rα) with cell-based activity. Starting with a low micromolar hit, we employed a combination of tethering, structural biology, and computa...
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| Veröffentlicht in: | Journal of the American Chemical Society 2003-04, Vol.125 (13), p.3714-3715 |
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| container_end_page | 3715 |
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| container_issue | 13 |
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| container_title | Journal of the American Chemical Society |
| container_volume | 125 |
| creator | Braisted, Andrew C Oslob, Johan D Delano, Warren L Hyde, Jennifer McDowell, Robert S Waal, Nathan Yu, Chul Arkin, Michelle R Raimundo, Brian C |
| description | Using a site-directed fragment discovery method called tethering, we have identified a 60 nM small molecule antagonist of a cytokine/receptor interaction (IL-2/IL2Rα) with cell-based activity. Starting with a low micromolar hit, we employed a combination of tethering, structural biology, and computational analysis to design a focused set of 20 compounds. Eight of these compounds were at least 5-fold more active than the original hit. One of these compounds showed a 50-fold enhancement and represents the highest affinity inhibitor reported against this protein−protein target class. This method of coupling selected fragments with a low micromolar hit shows great potential for generating high-affinity lead compounds. |
| doi_str_mv | 10.1021/ja034247i |
| format | Article |
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Am. Chem. Soc</addtitle><description>Using a site-directed fragment discovery method called tethering, we have identified a 60 nM small molecule antagonist of a cytokine/receptor interaction (IL-2/IL2Rα) with cell-based activity. Starting with a low micromolar hit, we employed a combination of tethering, structural biology, and computational analysis to design a focused set of 20 compounds. Eight of these compounds were at least 5-fold more active than the original hit. One of these compounds showed a 50-fold enhancement and represents the highest affinity inhibitor reported against this protein−protein target class. This method of coupling selected fragments with a low micromolar hit shows great potential for generating high-affinity lead compounds.</description><subject>Alkynes - chemistry</subject><subject>Alkynes - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Diverse techniques</subject><subject>Drug Design</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Interleukin-2 - antagonists & inhibitors</subject><subject>Interleukin-2 - chemistry</subject><subject>Interleukin-2 - metabolism</subject><subject>Interleukin-2 Receptor alpha Subunit</subject><subject>Kinetics</subject><subject>Models, Molecular</subject><subject>Molecular and cellular biology</subject><subject>Peptide Fragments - chemistry</subject><subject>Piperidines - chemistry</subject><subject>Piperidines - pharmacology</subject><subject>Protein Conformation</subject><subject>Receptors, Interleukin - agonists</subject><subject>Structure-Activity Relationship</subject><issn>0002-7863</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0E1PGzEQBmCrKiqB9tA_UPnSShyW-mNtb46IFAgKLRL00os18Y7Jpt41tXer5t93o0TkwskazaNX45eQj5ydcyb41zUwWYrSNG_IhCvBCsWFfksmjDFRmErLY3KS83ocS1Hxd-R4XCutptWE3M2a7OJfTBsaPQV6H3vsevrQQgj0LgZ0Q0A6XxSCzrtVs2z6mGi_SnF4WtGrBE_tll_kjO0ybN6TIw8h44f9e0p-Xn17vLwpFj-u55cXiwLKUvWFq72qGFQCawOGIePSgVdMiCmHqnLa10vBpCqnWCE4LT1wr7EWU4cSlJGn5Msu9znFPwPm3rbjNzAE6DAO2RrJpRaajfBsB12KOSf09jk1LaSN5cxuu7Mv3Y320z50WLZYH-S-rBF83gPIDoJP0LkmH1yplZBme12xc03u8d_LHtJvq400yj7eP1j96_b77GZ2bfkhF1y26zikbuzulQP_A-SNkNg</recordid><startdate>20030402</startdate><enddate>20030402</enddate><creator>Braisted, Andrew C</creator><creator>Oslob, Johan D</creator><creator>Delano, Warren L</creator><creator>Hyde, Jennifer</creator><creator>McDowell, Robert S</creator><creator>Waal, Nathan</creator><creator>Yu, Chul</creator><creator>Arkin, Michelle R</creator><creator>Raimundo, Brian C</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20030402</creationdate><title>Discovery of a Potent Small Molecule IL-2 Inhibitor through Fragment Assembly</title><author>Braisted, Andrew C ; Oslob, Johan D ; Delano, Warren L ; Hyde, Jennifer ; McDowell, Robert S ; Waal, Nathan ; Yu, Chul ; Arkin, Michelle R ; Raimundo, Brian C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a445t-cdf580a82ed7a70e013caf502291a88c6fdb203549e8eac63fa1f6ed29ce3a573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Alkynes - chemistry</topic><topic>Alkynes - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Diverse techniques</topic><topic>Drug Design</topic><topic>Fundamental and applied biological sciences. 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Am. Chem. Soc</addtitle><date>2003-04-02</date><risdate>2003</risdate><volume>125</volume><issue>13</issue><spage>3714</spage><epage>3715</epage><pages>3714-3715</pages><issn>0002-7863</issn><eissn>1520-5126</eissn><coden>JACSAT</coden><abstract>Using a site-directed fragment discovery method called tethering, we have identified a 60 nM small molecule antagonist of a cytokine/receptor interaction (IL-2/IL2Rα) with cell-based activity. Starting with a low micromolar hit, we employed a combination of tethering, structural biology, and computational analysis to design a focused set of 20 compounds. Eight of these compounds were at least 5-fold more active than the original hit. One of these compounds showed a 50-fold enhancement and represents the highest affinity inhibitor reported against this protein−protein target class. 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| subjects | Alkynes - chemistry Alkynes - pharmacology Biological and medical sciences Diverse techniques Drug Design Fundamental and applied biological sciences. Psychology Interleukin-2 - antagonists & inhibitors Interleukin-2 - chemistry Interleukin-2 - metabolism Interleukin-2 Receptor alpha Subunit Kinetics Models, Molecular Molecular and cellular biology Peptide Fragments - chemistry Piperidines - chemistry Piperidines - pharmacology Protein Conformation Receptors, Interleukin - agonists Structure-Activity Relationship |
| title | Discovery of a Potent Small Molecule IL-2 Inhibitor through Fragment Assembly |
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