The discovery of the potent aurora inhibitor MK-0457 (VX-680)
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR, which led to the discovery of MK-0457 (VX-680), is described. The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinaz...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2009-07, Vol.19 (13), p.3586-3592 |
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| creator | Bebbington, David Binch, Hayley Charrier, Jean-Damien Everitt, Simon Fraysse, Damien Golec, Julian Kay, David Knegtel, Ronald Mak, Chau Mazzei, Francesca Miller, Andrew Mortimore, Michael O’Donnell, Michael Patel, Sanjay Pierard, Francoise Pinder, Joanne Pollard, John Ramaya, Sharn Robinson, Daniel Rutherford, Alistair Studley, John Westcott, James |
| description | The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR, which led to the discovery of MK-0457 (VX-680), is described.
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph
+
ALL) containing the T315I mutation. |
| doi_str_mv | 10.1016/j.bmcl.2009.04.136 |
| format | Article |
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The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph
+
ALL) containing the T315I mutation.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2009.04.136</identifier><identifier>PMID: 19447622</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Antineoplastic agents ; Aurora ; Aurora Kinases ; Biological and medical sciences ; Cell Line, Tumor ; Computer Simulation ; Crystallography, X-Ray ; Drug Design ; General aspects ; Humans ; Kinase inhibitor ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy ; Medical sciences ; Mutant Proteins - antagonists & inhibitors ; Mutant Proteins - metabolism ; Pharmacology. Drug treatments ; Piperazines - chemistry ; Piperazines - pharmacology ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Protein Serine-Threonine Kinases - antagonists & inhibitors ; Protein Serine-Threonine Kinases - metabolism ; SAR ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2009-07, Vol.19 (13), p.3586-3592</ispartof><rights>2009 Elsevier Ltd</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c450t-bce9ad32e6f4a4c22de8ded2654dd93be90db4d0f4d920bf3ccafda8bb3e653e3</citedby><cites>FETCH-LOGICAL-c450t-bce9ad32e6f4a4c22de8ded2654dd93be90db4d0f4d920bf3ccafda8bb3e653e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X09006544$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21650130$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19447622$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bebbington, David</creatorcontrib><creatorcontrib>Binch, Hayley</creatorcontrib><creatorcontrib>Charrier, Jean-Damien</creatorcontrib><creatorcontrib>Everitt, Simon</creatorcontrib><creatorcontrib>Fraysse, Damien</creatorcontrib><creatorcontrib>Golec, Julian</creatorcontrib><creatorcontrib>Kay, David</creatorcontrib><creatorcontrib>Knegtel, Ronald</creatorcontrib><creatorcontrib>Mak, Chau</creatorcontrib><creatorcontrib>Mazzei, Francesca</creatorcontrib><creatorcontrib>Miller, Andrew</creatorcontrib><creatorcontrib>Mortimore, Michael</creatorcontrib><creatorcontrib>O’Donnell, Michael</creatorcontrib><creatorcontrib>Patel, Sanjay</creatorcontrib><creatorcontrib>Pierard, Francoise</creatorcontrib><creatorcontrib>Pinder, Joanne</creatorcontrib><creatorcontrib>Pollard, John</creatorcontrib><creatorcontrib>Ramaya, Sharn</creatorcontrib><creatorcontrib>Robinson, Daniel</creatorcontrib><creatorcontrib>Rutherford, Alistair</creatorcontrib><creatorcontrib>Studley, John</creatorcontrib><creatorcontrib>Westcott, James</creatorcontrib><title>The discovery of the potent aurora inhibitor MK-0457 (VX-680)</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR, which led to the discovery of MK-0457 (VX-680), is described.
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph
+
ALL) containing the T315I mutation.</description><subject>Antineoplastic agents</subject><subject>Aurora</subject><subject>Aurora Kinases</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>Computer Simulation</subject><subject>Crystallography, X-Ray</subject><subject>Drug Design</subject><subject>General aspects</subject><subject>Humans</subject><subject>Kinase inhibitor</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy</subject><subject>Medical sciences</subject><subject>Mutant Proteins - antagonists & inhibitors</subject><subject>Mutant Proteins - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperazines - chemistry</subject><subject>Piperazines - pharmacology</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>SAR</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtLJDEUhYOMaPv4Ay6G2sygiypvklvpLphZiPhCZTaOuAt53MI01ZWepFrw31tNN87O1YXLdw6Hj7ETDhUHrs7nlV24rhIATQVYcal22ISjwlIi1N_YBBoF5azBl312kPMcgCMg7rF93iBOlRAT9vvplQofsotvlN6L2BbD-FjGgfqhMKsUkylC_xpsGGIqHu9LwHpanD6_lGoGZ0dstzVdpuPtPWR_r6-eLm_Lhz83d5cXD6XDGobSOmqMl4JUiwadEJ5mnrxQNXrfSEsNeIseWvSNANtK50zrzcxaSaqWJA_Zz03vMsV_K8qDXoyTqetMT3GVtZpKqYDXIyg2oEsx50StXqawMOldc9BraXqu19L0WpoG1KO0MfR9276yC_L_I1tLI_BjC5jsTNcm07uQPznBVQ1cwsj92nA0ungLlHR2gXpHPiRyg_YxfLXjA6IOiUo</recordid><startdate>20090701</startdate><enddate>20090701</enddate><creator>Bebbington, David</creator><creator>Binch, Hayley</creator><creator>Charrier, Jean-Damien</creator><creator>Everitt, Simon</creator><creator>Fraysse, Damien</creator><creator>Golec, Julian</creator><creator>Kay, David</creator><creator>Knegtel, Ronald</creator><creator>Mak, Chau</creator><creator>Mazzei, Francesca</creator><creator>Miller, Andrew</creator><creator>Mortimore, Michael</creator><creator>O’Donnell, Michael</creator><creator>Patel, Sanjay</creator><creator>Pierard, Francoise</creator><creator>Pinder, Joanne</creator><creator>Pollard, John</creator><creator>Ramaya, Sharn</creator><creator>Robinson, Daniel</creator><creator>Rutherford, Alistair</creator><creator>Studley, John</creator><creator>Westcott, James</creator><general>Elsevier Ltd</general><general>Elsevier</general><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>20090701</creationdate><title>The discovery of the potent aurora inhibitor MK-0457 (VX-680)</title><author>Bebbington, David ; Binch, Hayley ; Charrier, Jean-Damien ; Everitt, Simon ; Fraysse, Damien ; Golec, Julian ; Kay, David ; Knegtel, Ronald ; Mak, Chau ; Mazzei, Francesca ; Miller, Andrew ; Mortimore, Michael ; O’Donnell, Michael ; Patel, Sanjay ; Pierard, Francoise ; Pinder, Joanne ; Pollard, John ; Ramaya, Sharn ; Robinson, Daniel ; Rutherford, Alistair ; Studley, John ; Westcott, James</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c450t-bce9ad32e6f4a4c22de8ded2654dd93be90db4d0f4d920bf3ccafda8bb3e653e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Antineoplastic agents</topic><topic>Aurora</topic><topic>Aurora Kinases</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>Computer Simulation</topic><topic>Crystallography, X-Ray</topic><topic>Drug Design</topic><topic>General aspects</topic><topic>Humans</topic><topic>Kinase inhibitor</topic><topic>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy</topic><topic>Medical sciences</topic><topic>Mutant Proteins - antagonists & inhibitors</topic><topic>Mutant Proteins - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperazines - chemistry</topic><topic>Piperazines - pharmacology</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>SAR</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bebbington, David</creatorcontrib><creatorcontrib>Binch, Hayley</creatorcontrib><creatorcontrib>Charrier, Jean-Damien</creatorcontrib><creatorcontrib>Everitt, Simon</creatorcontrib><creatorcontrib>Fraysse, Damien</creatorcontrib><creatorcontrib>Golec, Julian</creatorcontrib><creatorcontrib>Kay, David</creatorcontrib><creatorcontrib>Knegtel, Ronald</creatorcontrib><creatorcontrib>Mak, Chau</creatorcontrib><creatorcontrib>Mazzei, Francesca</creatorcontrib><creatorcontrib>Miller, Andrew</creatorcontrib><creatorcontrib>Mortimore, Michael</creatorcontrib><creatorcontrib>O’Donnell, Michael</creatorcontrib><creatorcontrib>Patel, Sanjay</creatorcontrib><creatorcontrib>Pierard, Francoise</creatorcontrib><creatorcontrib>Pinder, Joanne</creatorcontrib><creatorcontrib>Pollard, John</creatorcontrib><creatorcontrib>Ramaya, Sharn</creatorcontrib><creatorcontrib>Robinson, Daniel</creatorcontrib><creatorcontrib>Rutherford, Alistair</creatorcontrib><creatorcontrib>Studley, John</creatorcontrib><creatorcontrib>Westcott, James</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bebbington, David</au><au>Binch, Hayley</au><au>Charrier, Jean-Damien</au><au>Everitt, Simon</au><au>Fraysse, Damien</au><au>Golec, Julian</au><au>Kay, David</au><au>Knegtel, Ronald</au><au>Mak, Chau</au><au>Mazzei, Francesca</au><au>Miller, Andrew</au><au>Mortimore, Michael</au><au>O’Donnell, Michael</au><au>Patel, Sanjay</au><au>Pierard, Francoise</au><au>Pinder, Joanne</au><au>Pollard, John</au><au>Ramaya, Sharn</au><au>Robinson, Daniel</au><au>Rutherford, Alistair</au><au>Studley, John</au><au>Westcott, James</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The discovery of the potent aurora inhibitor MK-0457 (VX-680)</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2009-07-01</date><risdate>2009</risdate><volume>19</volume><issue>13</issue><spage>3586</spage><epage>3592</epage><pages>3586-3592</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR, which led to the discovery of MK-0457 (VX-680), is described.
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph
+
ALL) containing the T315I mutation.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>19447622</pmid><doi>10.1016/j.bmcl.2009.04.136</doi><tpages>7</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2009-07, Vol.19 (13), p.3586-3592 |
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| subjects | Antineoplastic agents Aurora Aurora Kinases Biological and medical sciences Cell Line, Tumor Computer Simulation Crystallography, X-Ray Drug Design General aspects Humans Kinase inhibitor Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy Medical sciences Mutant Proteins - antagonists & inhibitors Mutant Proteins - metabolism Pharmacology. Drug treatments Piperazines - chemistry Piperazines - pharmacology Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - metabolism SAR Structure-Activity Relationship |
| title | The discovery of the potent aurora inhibitor MK-0457 (VX-680) |
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