Discovery of 3‑(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl‑3H‑imidazo[4,5‑b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor
The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT...
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| Veröffentlicht in: | Journal of medicinal chemistry 2016-07, Vol.59 (13), p.6455-6469 |
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| creator | Lapierre, Jean-Marc Eathiraj, Sudharshan Vensel, David Liu, Yanbin Bull, Cathy O Cornell-Kennon, Susan Iimura, Shin Kelleher, Eugene W Kizer, Darin E Koerner, Steffi Makhija, Sapna Matsuda, Akihisa Moussa, Magdi Namdev, Nivedita Savage, Ronald E Szwaya, Jeff Volckova, Erika Westlund, Neil Wu, Hui Schwartz, Brian |
| description | The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma. |
| doi_str_mv | 10.1021/acs.jmedchem.6b00619 |
| format | Article |
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The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.6b00619</identifier><identifier>PMID: 27305487</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Administration, Oral ; Allosteric Regulation - drug effects ; Aminopyridines - administration & dosage ; Aminopyridines - chemistry ; Aminopyridines - pharmacology ; Animals ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Carcinoma, Endometrioid - drug therapy ; Carcinoma, Endometrioid - pathology ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Drug Discovery ; Drug Screening Assays, Antitumor ; Endometrial Neoplasms - drug therapy ; Endometrial Neoplasms - pathology ; Female ; Humans ; Imidazoles - administration & dosage ; Imidazoles - chemistry ; Imidazoles - pharmacology ; Mice ; Molecular Structure ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - pathology ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2016-07, Vol.59 (13), p.6455-6469</ispartof><rights>Copyright © 2016 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.6b00619$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.6b00619$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27305487$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lapierre, Jean-Marc</creatorcontrib><creatorcontrib>Eathiraj, Sudharshan</creatorcontrib><creatorcontrib>Vensel, David</creatorcontrib><creatorcontrib>Liu, Yanbin</creatorcontrib><creatorcontrib>Bull, Cathy O</creatorcontrib><creatorcontrib>Cornell-Kennon, Susan</creatorcontrib><creatorcontrib>Iimura, Shin</creatorcontrib><creatorcontrib>Kelleher, Eugene W</creatorcontrib><creatorcontrib>Kizer, Darin E</creatorcontrib><creatorcontrib>Koerner, Steffi</creatorcontrib><creatorcontrib>Makhija, Sapna</creatorcontrib><creatorcontrib>Matsuda, Akihisa</creatorcontrib><creatorcontrib>Moussa, Magdi</creatorcontrib><creatorcontrib>Namdev, Nivedita</creatorcontrib><creatorcontrib>Savage, Ronald E</creatorcontrib><creatorcontrib>Szwaya, Jeff</creatorcontrib><creatorcontrib>Volckova, Erika</creatorcontrib><creatorcontrib>Westlund, Neil</creatorcontrib><creatorcontrib>Wu, Hui</creatorcontrib><creatorcontrib>Schwartz, Brian</creatorcontrib><title>Discovery of 3‑(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl‑3H‑imidazo[4,5‑b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.</description><subject>Administration, Oral</subject><subject>Allosteric Regulation - drug effects</subject><subject>Aminopyridines - administration & dosage</subject><subject>Aminopyridines - chemistry</subject><subject>Aminopyridines - pharmacology</subject><subject>Animals</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Carcinoma, Endometrioid - drug therapy</subject><subject>Carcinoma, Endometrioid - pathology</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Endometrial Neoplasms - drug therapy</subject><subject>Endometrial Neoplasms - pathology</subject><subject>Female</subject><subject>Humans</subject><subject>Imidazoles - administration & dosage</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacology</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kdtu1DAQhi0EokvhDRDyZSrVy_iUA3ehHFpRqRzKFUKR7Thar5x4cZKVwhWvwBvxLDwJLrtw45mxPo-s_0PoKYU1BUafKzOut71tzcb261wD5LS6h1ZUMiCiBHEfrQAYIyxn_AQ9GsctAHDK-EN0wgoOUpTFCv165UYT9jYuOHSY__7xM-MkEySjpO7dEMxifNDztPiz3cYOqRBJDl1i-WU6XO9a9T18EecyTfrrbomudQNh5O7R_0GldRZn9ccPGCp29gLXA76JyvsFv3RB7ZXzSnt7jj9Zb83k9qlVQ4vfh8kOE669D-NkozO4fneLr4aN024K8TF60Ck_2ifHeoo-v3l9e3FJrm_eXl3U10RxWk6ko11VARhhrGo1h8K0uSq4KqWWbdvleVUILbmgvINKS2WlEaALJitptKWSn6LssHcXw7fZjlPTp-Ss92qwYR4bmiIvpZCiSOizIzrrJKjZRderuDT_Uk8AHIDksNmGOQ7p5w2F5k5s8_fyKLY5iuV_AHAHmgA</recordid><startdate>20160714</startdate><enddate>20160714</enddate><creator>Lapierre, Jean-Marc</creator><creator>Eathiraj, Sudharshan</creator><creator>Vensel, David</creator><creator>Liu, Yanbin</creator><creator>Bull, Cathy O</creator><creator>Cornell-Kennon, Susan</creator><creator>Iimura, Shin</creator><creator>Kelleher, Eugene W</creator><creator>Kizer, Darin E</creator><creator>Koerner, Steffi</creator><creator>Makhija, Sapna</creator><creator>Matsuda, Akihisa</creator><creator>Moussa, Magdi</creator><creator>Namdev, Nivedita</creator><creator>Savage, Ronald E</creator><creator>Szwaya, Jeff</creator><creator>Volckova, Erika</creator><creator>Westlund, Neil</creator><creator>Wu, Hui</creator><creator>Schwartz, Brian</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20160714</creationdate><title>Discovery of 3‑(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl‑3H‑imidazo[4,5‑b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor</title><author>Lapierre, Jean-Marc ; Eathiraj, Sudharshan ; Vensel, David ; Liu, Yanbin ; Bull, Cathy O ; Cornell-Kennon, Susan ; Iimura, Shin ; Kelleher, Eugene W ; Kizer, Darin E ; Koerner, Steffi ; Makhija, Sapna ; Matsuda, Akihisa ; Moussa, Magdi ; Namdev, Nivedita ; Savage, Ronald E ; Szwaya, Jeff ; Volckova, Erika ; Westlund, Neil ; Wu, Hui ; Schwartz, Brian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a318t-f1f9900c4ceadb307cd6a73a85b5ddf66974b53413f09b5ae5c40b72595cbe153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Administration, Oral</topic><topic>Allosteric Regulation - drug effects</topic><topic>Aminopyridines - administration & dosage</topic><topic>Aminopyridines - chemistry</topic><topic>Aminopyridines - pharmacology</topic><topic>Animals</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Carcinoma, Endometrioid - drug therapy</topic><topic>Carcinoma, Endometrioid - pathology</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Endometrial Neoplasms - drug therapy</topic><topic>Endometrial Neoplasms - pathology</topic><topic>Female</topic><topic>Humans</topic><topic>Imidazoles - administration & dosage</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacology</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - pathology</topic><topic>Protein Kinase Inhibitors - administration & dosage</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lapierre, Jean-Marc</creatorcontrib><creatorcontrib>Eathiraj, Sudharshan</creatorcontrib><creatorcontrib>Vensel, David</creatorcontrib><creatorcontrib>Liu, Yanbin</creatorcontrib><creatorcontrib>Bull, Cathy O</creatorcontrib><creatorcontrib>Cornell-Kennon, Susan</creatorcontrib><creatorcontrib>Iimura, Shin</creatorcontrib><creatorcontrib>Kelleher, Eugene W</creatorcontrib><creatorcontrib>Kizer, Darin E</creatorcontrib><creatorcontrib>Koerner, Steffi</creatorcontrib><creatorcontrib>Makhija, Sapna</creatorcontrib><creatorcontrib>Matsuda, Akihisa</creatorcontrib><creatorcontrib>Moussa, Magdi</creatorcontrib><creatorcontrib>Namdev, Nivedita</creatorcontrib><creatorcontrib>Savage, Ronald E</creatorcontrib><creatorcontrib>Szwaya, Jeff</creatorcontrib><creatorcontrib>Volckova, Erika</creatorcontrib><creatorcontrib>Westlund, Neil</creatorcontrib><creatorcontrib>Wu, Hui</creatorcontrib><creatorcontrib>Schwartz, Brian</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>Lapierre, Jean-Marc</au><au>Eathiraj, Sudharshan</au><au>Vensel, David</au><au>Liu, Yanbin</au><au>Bull, Cathy O</au><au>Cornell-Kennon, Susan</au><au>Iimura, Shin</au><au>Kelleher, Eugene W</au><au>Kizer, Darin E</au><au>Koerner, Steffi</au><au>Makhija, Sapna</au><au>Matsuda, Akihisa</au><au>Moussa, Magdi</au><au>Namdev, Nivedita</au><au>Savage, Ronald E</au><au>Szwaya, Jeff</au><au>Volckova, Erika</au><au>Westlund, Neil</au><au>Wu, Hui</au><au>Schwartz, Brian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of 3‑(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl‑3H‑imidazo[4,5‑b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2016-07-14</date><risdate>2016</risdate><volume>59</volume><issue>13</issue><spage>6455</spage><epage>6469</epage><pages>6455-6469</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>27305487</pmid><doi>10.1021/acs.jmedchem.6b00619</doi><tpages>15</tpages></addata></record> |
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| source | ACS Publications; MEDLINE |
| subjects | Administration, Oral Allosteric Regulation - drug effects Aminopyridines - administration & dosage Aminopyridines - chemistry Aminopyridines - pharmacology Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Carcinoma, Endometrioid - drug therapy Carcinoma, Endometrioid - pathology Cell Proliferation - drug effects Dose-Response Relationship, Drug Drug Discovery Drug Screening Assays, Antitumor Endometrial Neoplasms - drug therapy Endometrial Neoplasms - pathology Female Humans Imidazoles - administration & dosage Imidazoles - chemistry Imidazoles - pharmacology Mice Molecular Structure Neoplasms, Experimental - drug therapy Neoplasms, Experimental - pathology Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Structure-Activity Relationship |
| title | Discovery of 3‑(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl‑3H‑imidazo[4,5‑b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor |
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