Inhibitors of p21-activated kinases (PAKs)
The p21-activated kinase (PAK) family of serine/threonine protein kinases plays important roles in cytoskeletal organization, cellular morphogenesis, and survival, and members of this family have been implicated in many diseases including cancer, infectious diseases, and neurological disorders. Owin...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-01, Vol.58 (1), p.111-129 |
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| container_end_page | 129 |
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| container_title | Journal of medicinal chemistry |
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| creator | Rudolph, Joachim Crawford, James J Hoeflich, Klaus P Wang, Weiru |
| description | The p21-activated kinase (PAK) family of serine/threonine protein kinases plays important roles in cytoskeletal organization, cellular morphogenesis, and survival, and members of this family have been implicated in many diseases including cancer, infectious diseases, and neurological disorders. Owing to their large and flexible ATP binding cleft, PAKs, particularly group I PAKs (PAK1, -2, and -3), are difficult to drug; hence, few PAK inhibitors with satisfactory kinase selectivity and druglike properties have been reported to date. Examples are a recently discovered group II PAK (PAK4, -5, -6) selective inhibitor series based on a benzimidazole core, a group I PAK selective series based on a pyrido[2,3-d]pyrimidine-7-one core, and an allosteric dibenzodiazepine PAK1 inhibitor series. Only one compound, an aminopyrazole based pan-PAK inhibitor, entered clinical trials but did not progress beyond phase I trials. Clinical proof of concept for pan-group I, pan-group II, or PAK isoform selective inhibition has yet to be demonstrated. |
| doi_str_mv | 10.1021/jm501613q |
| format | Article |
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Owing to their large and flexible ATP binding cleft, PAKs, particularly group I PAKs (PAK1, -2, and -3), are difficult to drug; hence, few PAK inhibitors with satisfactory kinase selectivity and druglike properties have been reported to date. Examples are a recently discovered group II PAK (PAK4, -5, -6) selective inhibitor series based on a benzimidazole core, a group I PAK selective series based on a pyrido[2,3-d]pyrimidine-7-one core, and an allosteric dibenzodiazepine PAK1 inhibitor series. Only one compound, an aminopyrazole based pan-PAK inhibitor, entered clinical trials but did not progress beyond phase I trials. Clinical proof of concept for pan-group I, pan-group II, or PAK isoform selective inhibition has yet to be demonstrated.</description><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm501613q</identifier><identifier>PMID: 25415869</identifier><language>eng</language><publisher>United States</publisher><subject>Cell Proliferation - drug effects ; Cell Survival - drug effects ; Humans ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - chemistry ; Isoenzymes - metabolism ; Models, Biological ; Models, Molecular ; Molecular Structure ; Neoplasms - drug therapy ; Neoplasms - pathology ; p21-Activated Kinases - antagonists & inhibitors ; p21-Activated Kinases - chemistry ; p21-Activated Kinases - metabolism ; Protein Binding ; Protein Isoforms - antagonists & inhibitors ; Protein Isoforms - metabolism ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - metabolism ; Protein Kinase Inhibitors - pharmacology ; Protein Structure, Tertiary ; Signal Transduction - drug effects</subject><ispartof>Journal of medicinal chemistry, 2015-01, Vol.58 (1), p.111-129</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25415869$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rudolph, Joachim</creatorcontrib><creatorcontrib>Crawford, James J</creatorcontrib><creatorcontrib>Hoeflich, Klaus P</creatorcontrib><creatorcontrib>Wang, Weiru</creatorcontrib><title>Inhibitors of p21-activated kinases (PAKs)</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>The p21-activated kinase (PAK) family of serine/threonine protein kinases plays important roles in cytoskeletal organization, cellular morphogenesis, and survival, and members of this family have been implicated in many diseases including cancer, infectious diseases, and neurological disorders. Owing to their large and flexible ATP binding cleft, PAKs, particularly group I PAKs (PAK1, -2, and -3), are difficult to drug; hence, few PAK inhibitors with satisfactory kinase selectivity and druglike properties have been reported to date. Examples are a recently discovered group II PAK (PAK4, -5, -6) selective inhibitor series based on a benzimidazole core, a group I PAK selective series based on a pyrido[2,3-d]pyrimidine-7-one core, and an allosteric dibenzodiazepine PAK1 inhibitor series. Only one compound, an aminopyrazole based pan-PAK inhibitor, entered clinical trials but did not progress beyond phase I trials. Clinical proof of concept for pan-group I, pan-group II, or PAK isoform selective inhibition has yet to be demonstrated.</description><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Humans</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - chemistry</subject><subject>Isoenzymes - metabolism</subject><subject>Models, Biological</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - pathology</subject><subject>p21-Activated Kinases - antagonists & inhibitors</subject><subject>p21-Activated Kinases - chemistry</subject><subject>p21-Activated Kinases - metabolism</subject><subject>Protein Binding</subject><subject>Protein Isoforms - antagonists & inhibitors</subject><subject>Protein Isoforms - metabolism</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - metabolism</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Structure, Tertiary</subject><subject>Signal Transduction - drug effects</subject><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1j81KAzEYRYMgtlYXvoDMsgqj35ffybKUqsWCLnQ9JJMEU-evk6ng21uxri5czrlwCblCuEOgeL9tBKBEtjshUxQUcl4An5DzlLYAwJCyMzKhgqMopJ6S23X7EW0cuyFlXch6irmpxvhlRu-yz9ia5FM2f108p5sLchpMnfzlMWfk_WH1tnzKNy-P6-Vikx9kHHOvBAI4HarKam6NLdApikq6ImgTnBTGmqC0k77wh945J3UhQDlkWhvJZmT-t9sP3W7v01g2MVW-rk3ru30qUXKhFAf2i14f0b1tvCv7ITZm-C7__7EfuzJNLw</recordid><startdate>20150108</startdate><enddate>20150108</enddate><creator>Rudolph, Joachim</creator><creator>Crawford, James J</creator><creator>Hoeflich, Klaus P</creator><creator>Wang, Weiru</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20150108</creationdate><title>Inhibitors of p21-activated kinases (PAKs)</title><author>Rudolph, Joachim ; Crawford, James J ; Hoeflich, Klaus P ; Wang, Weiru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p211t-e75100d9fccb94bab81d72176d8f9afd65abaf79d6e8e217ddd698507d1399a63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Humans</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Isoenzymes - chemistry</topic><topic>Isoenzymes - metabolism</topic><topic>Models, Biological</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - pathology</topic><topic>p21-Activated Kinases - antagonists & inhibitors</topic><topic>p21-Activated Kinases - chemistry</topic><topic>p21-Activated Kinases - metabolism</topic><topic>Protein Binding</topic><topic>Protein Isoforms - antagonists & inhibitors</topic><topic>Protein Isoforms - metabolism</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - metabolism</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Structure, Tertiary</topic><topic>Signal Transduction - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rudolph, Joachim</creatorcontrib><creatorcontrib>Crawford, James J</creatorcontrib><creatorcontrib>Hoeflich, Klaus P</creatorcontrib><creatorcontrib>Wang, Weiru</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rudolph, Joachim</au><au>Crawford, James J</au><au>Hoeflich, Klaus P</au><au>Wang, Weiru</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibitors of p21-activated kinases (PAKs)</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2015-01-08</date><risdate>2015</risdate><volume>58</volume><issue>1</issue><spage>111</spage><epage>129</epage><pages>111-129</pages><eissn>1520-4804</eissn><abstract>The p21-activated kinase (PAK) family of serine/threonine protein kinases plays important roles in cytoskeletal organization, cellular morphogenesis, and survival, and members of this family have been implicated in many diseases including cancer, infectious diseases, and neurological disorders. 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| subjects | Cell Proliferation - drug effects Cell Survival - drug effects Humans Isoenzymes - antagonists & inhibitors Isoenzymes - chemistry Isoenzymes - metabolism Models, Biological Models, Molecular Molecular Structure Neoplasms - drug therapy Neoplasms - pathology p21-Activated Kinases - antagonists & inhibitors p21-Activated Kinases - chemistry p21-Activated Kinases - metabolism Protein Binding Protein Isoforms - antagonists & inhibitors Protein Isoforms - metabolism Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Kinase Inhibitors - pharmacology Protein Structure, Tertiary Signal Transduction - drug effects |
| title | Inhibitors of p21-activated kinases (PAKs) |
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