Drugging all RAS isoforms with one pocket
Activating mutations in the three human RAS genes, , and , are among the most common oncogenic drivers in human cancers. Covalent KRAS inhibitors, which bind to the switch II pocket in the ‘off state’ of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the rem...
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| Veröffentlicht in: | Future medicinal chemistry 2020-11, Vol.12 (21), p.1911-1923 |
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| container_issue | 21 |
| container_start_page | 1911 |
| container_title | Future medicinal chemistry |
| container_volume | 12 |
| creator | Kessler, Dirk Bergner, Andreas Böttcher, Jark Fischer, Gerhard Döbel, Sandra Hinkel, Melanie Müllauer, Barbara Weiss-Puxbaum, Alexander McConnell, Darryl B |
| description | Activating mutations in the three human RAS genes,
,
and
, are among the most common oncogenic drivers in human cancers. Covalent KRAS
inhibitors, which bind to the switch II pocket in the ‘off state’ of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRAS
-driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the ‘on state’ have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket. |
| doi_str_mv | 10.4155/fmc-2020-0221 |
| format | Article |
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,
and
, are among the most common oncogenic drivers in human cancers. Covalent KRAS
inhibitors, which bind to the switch II pocket in the ‘off state’ of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRAS
-driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the ‘on state’ have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket.</description><identifier>ISSN: 1756-8919</identifier><identifier>EISSN: 1756-8927</identifier><identifier>DOI: 10.4155/fmc-2020-0221</identifier><identifier>PMID: 32779487</identifier><language>eng</language><publisher>England: Newlands Press Ltd</publisher><subject>Amino acids ; BI-2852 ; Binding sites ; Cell growth ; Clinical trials ; Drug delivery ; GTPase ; Isoforms ; KRAS ; Ligands ; Mutation ; NMR ; Nuclear magnetic resonance ; Proteins ; Signal transduction ; small molecule inhibitors</subject><ispartof>Future medicinal chemistry, 2020-11, Vol.12 (21), p.1911-1923</ispartof><rights>2020 Boehringer Ingelheim RCY GmbH & Co KG</rights><rights>Copyright Newlands Press Nov 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c410t-c6f9813e5a95753e9677e42adc5d7285c617503efffe1708f989f6d07aaf4cd23</citedby><cites>FETCH-LOGICAL-c410t-c6f9813e5a95753e9677e42adc5d7285c617503efffe1708f989f6d07aaf4cd23</cites><orcidid>0000-0001-6808-9011 ; 0000-0003-2189-5926 ; 0000-0002-2537-3458 ; 0000-0002-5843-4325 ; 0000-0001-9861-1528 ; 0000-0002-0966-8045</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32779487$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kessler, Dirk</creatorcontrib><creatorcontrib>Bergner, Andreas</creatorcontrib><creatorcontrib>Böttcher, Jark</creatorcontrib><creatorcontrib>Fischer, Gerhard</creatorcontrib><creatorcontrib>Döbel, Sandra</creatorcontrib><creatorcontrib>Hinkel, Melanie</creatorcontrib><creatorcontrib>Müllauer, Barbara</creatorcontrib><creatorcontrib>Weiss-Puxbaum, Alexander</creatorcontrib><creatorcontrib>McConnell, Darryl B</creatorcontrib><title>Drugging all RAS isoforms with one pocket</title><title>Future medicinal chemistry</title><addtitle>Future Med Chem</addtitle><description>Activating mutations in the three human RAS genes,
,
and
, are among the most common oncogenic drivers in human cancers. Covalent KRAS
inhibitors, which bind to the switch II pocket in the ‘off state’ of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRAS
-driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the ‘on state’ have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket.</description><subject>Amino acids</subject><subject>BI-2852</subject><subject>Binding sites</subject><subject>Cell growth</subject><subject>Clinical trials</subject><subject>Drug delivery</subject><subject>GTPase</subject><subject>Isoforms</subject><subject>KRAS</subject><subject>Ligands</subject><subject>Mutation</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Proteins</subject><subject>Signal transduction</subject><subject>small molecule inhibitors</subject><issn>1756-8919</issn><issn>1756-8927</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp10EtLAzEUBeAgii21S7cy4EYXo0kmj8my-IaC4GMdYuamps6jJjOI_96U1i4Es0kCXw43B6Fjgi8Y4fzSNTanmOIcU0r20JhILvJSUbm_OxM1QtMYlzitgpZK8EM0KqiUipVyjM6vw7BY-HaRmbrOnmbPmY-d60ITsy_fv2ddC9mqsx_QH6EDZ-oI0-0-Qa-3Ny9X9_n88e7hajbPLSO4z61wqiQFcKO45AUoISUwairLK0lLbkUaDBfgnAMicZm0cqLC0hjHbEWLCTrb5K5C9zlA7HXjo4W6Ni10Q9SUpW9wxhRJ9PQPXXZDaNN0mnKSnGRCJJVvlA1djAGcXgXfmPCtCdbrGnWqUa9r1Osakz_Zpg5vDVQ7_VtaAmoD3NAPAaL10FrQm1t64a1v4Z_wH1tkfic</recordid><startdate>20201101</startdate><enddate>20201101</enddate><creator>Kessler, Dirk</creator><creator>Bergner, Andreas</creator><creator>Böttcher, Jark</creator><creator>Fischer, Gerhard</creator><creator>Döbel, Sandra</creator><creator>Hinkel, Melanie</creator><creator>Müllauer, Barbara</creator><creator>Weiss-Puxbaum, Alexander</creator><creator>McConnell, Darryl B</creator><general>Newlands Press Ltd</general><general>Newlands Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6808-9011</orcidid><orcidid>https://orcid.org/0000-0003-2189-5926</orcidid><orcidid>https://orcid.org/0000-0002-2537-3458</orcidid><orcidid>https://orcid.org/0000-0002-5843-4325</orcidid><orcidid>https://orcid.org/0000-0001-9861-1528</orcidid><orcidid>https://orcid.org/0000-0002-0966-8045</orcidid></search><sort><creationdate>20201101</creationdate><title>Drugging all RAS isoforms with one pocket</title><author>Kessler, Dirk ; Bergner, Andreas ; Böttcher, Jark ; Fischer, Gerhard ; Döbel, Sandra ; Hinkel, Melanie ; Müllauer, Barbara ; Weiss-Puxbaum, Alexander ; McConnell, Darryl B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c410t-c6f9813e5a95753e9677e42adc5d7285c617503efffe1708f989f6d07aaf4cd23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Amino acids</topic><topic>BI-2852</topic><topic>Binding sites</topic><topic>Cell growth</topic><topic>Clinical trials</topic><topic>Drug delivery</topic><topic>GTPase</topic><topic>Isoforms</topic><topic>KRAS</topic><topic>Ligands</topic><topic>Mutation</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Proteins</topic><topic>Signal transduction</topic><topic>small molecule inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kessler, Dirk</creatorcontrib><creatorcontrib>Bergner, Andreas</creatorcontrib><creatorcontrib>Böttcher, Jark</creatorcontrib><creatorcontrib>Fischer, Gerhard</creatorcontrib><creatorcontrib>Döbel, Sandra</creatorcontrib><creatorcontrib>Hinkel, Melanie</creatorcontrib><creatorcontrib>Müllauer, Barbara</creatorcontrib><creatorcontrib>Weiss-Puxbaum, Alexander</creatorcontrib><creatorcontrib>McConnell, Darryl B</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Future medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kessler, Dirk</au><au>Bergner, Andreas</au><au>Böttcher, Jark</au><au>Fischer, Gerhard</au><au>Döbel, Sandra</au><au>Hinkel, Melanie</au><au>Müllauer, Barbara</au><au>Weiss-Puxbaum, Alexander</au><au>McConnell, Darryl B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Drugging all RAS isoforms with one pocket</atitle><jtitle>Future medicinal chemistry</jtitle><addtitle>Future Med Chem</addtitle><date>2020-11-01</date><risdate>2020</risdate><volume>12</volume><issue>21</issue><spage>1911</spage><epage>1923</epage><pages>1911-1923</pages><issn>1756-8919</issn><eissn>1756-8927</eissn><abstract>Activating mutations in the three human RAS genes,
,
and
, are among the most common oncogenic drivers in human cancers. Covalent KRAS
inhibitors, which bind to the switch II pocket in the ‘off state’ of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRAS
-driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the ‘on state’ have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket.</abstract><cop>England</cop><pub>Newlands Press Ltd</pub><pmid>32779487</pmid><doi>10.4155/fmc-2020-0221</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-6808-9011</orcidid><orcidid>https://orcid.org/0000-0003-2189-5926</orcidid><orcidid>https://orcid.org/0000-0002-2537-3458</orcidid><orcidid>https://orcid.org/0000-0002-5843-4325</orcidid><orcidid>https://orcid.org/0000-0001-9861-1528</orcidid><orcidid>https://orcid.org/0000-0002-0966-8045</orcidid><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | PubMed Central |
| subjects | Amino acids BI-2852 Binding sites Cell growth Clinical trials Drug delivery GTPase Isoforms KRAS Ligands Mutation NMR Nuclear magnetic resonance Proteins Signal transduction small molecule inhibitors |
| title | Drugging all RAS isoforms with one pocket |
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