Discovery of 6‑[(3S,4S)‑4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor
Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfe...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2021-10, Vol.64 (20), p.15141-15169 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 15169 |
|---|---|
| container_issue | 20 |
| container_start_page | 15141 |
| container_title | Journal of medicinal chemistry |
| container_volume | 64 |
| creator | Czako, Barbara Sun, Yuting McAfoos, Timothy Cross, Jason B Leonard, Paul G Burke, Jason P Carroll, Christopher L Feng, Ningping Harris, Angela L Jiang, Yongying Kang, Zhijun Kovacs, Jeffrey J Mandal, Pijus Meyers, Brooke A Mseeh, Faika Parker, Connor A Yu, Simon S Williams, Christopher C Wu, Qi Di Francesco, Maria Emilia Draetta, Giulio Heffernan, Timothy Marszalek, Joseph. R Kohl, Nancy E Jones, Philip |
| description | Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo. |
| doi_str_mv | 10.1021/acs.jmedchem.1c01132 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2581826019</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2581826019</sourcerecordid><originalsourceid>FETCH-LOGICAL-a348t-8c277cbed5280fff0568559519f8ce21abd95fa9dc76b59982f5fb79ab30e9be3</originalsourceid><addsrcrecordid>eNp9kUtuEzEYxy1ERUPhBgh5mUhx8HNiL9PwaKRKrRRYVdXI47E1rjzj4JlUDCuuwKV6kJ4EQ9IuWdny__Hp8w-AdwQvCKbkgzb94q61tWlsuyAGE8LoCzAhgmLEJeYvwQRjShEtKDsFr_v-DmPMCGWvwCnjBWdM4Ql4-Oh7E-9tGmF0sHj89ftmyrZzvp3lK0er1ncRMdTaoRkDoij-0Egi_VP3O5_iDV-I29oa3eXHMdxm55TOGaq9aUJMcdfYbgyznDsWsDnPYjPWWRuTb33tO8RR7CycblbrLSKCEz6bQw2v42C7AequhldJhzDCcx_1vfZBV8HC7cU1hZuu8ZUfYnoDTpwOvX17PM_At8-fvq4v0OXVl816dYk043JA0tDl0lS2FlRi5xwWhRRCCaKcNJYSXdVKOK1qsywqoZSkTrhqqXTFsFWVZWdgeujdpfh9b_uhbPP_2RB0Z-O-L6mQRNICE5Wt_GA1KfZ9sq7c5YV1GkuCy78Ey0ywfCJYHgnm2PvjhH2VtefQE7JswAfDv3jcpy4v_P_OP5DxqcI</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2581826019</pqid></control><display><type>article</type><title>Discovery of 6‑[(3S,4S)‑4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor</title><source>ACS Publications</source><source>MEDLINE</source><creator>Czako, Barbara ; Sun, Yuting ; McAfoos, Timothy ; Cross, Jason B ; Leonard, Paul G ; Burke, Jason P ; Carroll, Christopher L ; Feng, Ningping ; Harris, Angela L ; Jiang, Yongying ; Kang, Zhijun ; Kovacs, Jeffrey J ; Mandal, Pijus ; Meyers, Brooke A ; Mseeh, Faika ; Parker, Connor A ; Yu, Simon S ; Williams, Christopher C ; Wu, Qi ; Di Francesco, Maria Emilia ; Draetta, Giulio ; Heffernan, Timothy ; Marszalek, Joseph. R ; Kohl, Nancy E ; Jones, Philip</creator><creatorcontrib>Czako, Barbara ; Sun, Yuting ; McAfoos, Timothy ; Cross, Jason B ; Leonard, Paul G ; Burke, Jason P ; Carroll, Christopher L ; Feng, Ningping ; Harris, Angela L ; Jiang, Yongying ; Kang, Zhijun ; Kovacs, Jeffrey J ; Mandal, Pijus ; Meyers, Brooke A ; Mseeh, Faika ; Parker, Connor A ; Yu, Simon S ; Williams, Christopher C ; Wu, Qi ; Di Francesco, Maria Emilia ; Draetta, Giulio ; Heffernan, Timothy ; Marszalek, Joseph. R ; Kohl, Nancy E ; Jones, Philip</creatorcontrib><description>Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c01132</identifier><identifier>PMID: 34643390</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Administration, Oral ; Animals ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Drug Discovery ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors - administration & dosage ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Humans ; Mice ; Molecular Structure ; Neoplasms, Experimental - drug therapy ; Neoplasms, Experimental - metabolism ; Neoplasms, Experimental - pathology ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2021-10, Vol.64 (20), p.15141-15169</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-8c277cbed5280fff0568559519f8ce21abd95fa9dc76b59982f5fb79ab30e9be3</citedby><cites>FETCH-LOGICAL-a348t-8c277cbed5280fff0568559519f8ce21abd95fa9dc76b59982f5fb79ab30e9be3</cites><orcidid>0000-0002-3357-7514</orcidid></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.1c01132$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01132$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34643390$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Czako, Barbara</creatorcontrib><creatorcontrib>Sun, Yuting</creatorcontrib><creatorcontrib>McAfoos, Timothy</creatorcontrib><creatorcontrib>Cross, Jason B</creatorcontrib><creatorcontrib>Leonard, Paul G</creatorcontrib><creatorcontrib>Burke, Jason P</creatorcontrib><creatorcontrib>Carroll, Christopher L</creatorcontrib><creatorcontrib>Feng, Ningping</creatorcontrib><creatorcontrib>Harris, Angela L</creatorcontrib><creatorcontrib>Jiang, Yongying</creatorcontrib><creatorcontrib>Kang, Zhijun</creatorcontrib><creatorcontrib>Kovacs, Jeffrey J</creatorcontrib><creatorcontrib>Mandal, Pijus</creatorcontrib><creatorcontrib>Meyers, Brooke A</creatorcontrib><creatorcontrib>Mseeh, Faika</creatorcontrib><creatorcontrib>Parker, Connor A</creatorcontrib><creatorcontrib>Yu, Simon S</creatorcontrib><creatorcontrib>Williams, Christopher C</creatorcontrib><creatorcontrib>Wu, Qi</creatorcontrib><creatorcontrib>Di Francesco, Maria Emilia</creatorcontrib><creatorcontrib>Draetta, Giulio</creatorcontrib><creatorcontrib>Heffernan, Timothy</creatorcontrib><creatorcontrib>Marszalek, Joseph. R</creatorcontrib><creatorcontrib>Kohl, Nancy E</creatorcontrib><creatorcontrib>Jones, Philip</creatorcontrib><title>Discovery of 6‑[(3S,4S)‑4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Enzyme Inhibitors - administration & dosage</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - metabolism</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtuEzEYxy1ERUPhBgh5mUhx8HNiL9PwaKRKrRRYVdXI47E1rjzj4JlUDCuuwKV6kJ4EQ9IuWdny__Hp8w-AdwQvCKbkgzb94q61tWlsuyAGE8LoCzAhgmLEJeYvwQRjShEtKDsFr_v-DmPMCGWvwCnjBWdM4Ql4-Oh7E-9tGmF0sHj89ftmyrZzvp3lK0er1ncRMdTaoRkDoij-0Egi_VP3O5_iDV-I29oa3eXHMdxm55TOGaq9aUJMcdfYbgyznDsWsDnPYjPWWRuTb33tO8RR7CycblbrLSKCEz6bQw2v42C7AequhldJhzDCcx_1vfZBV8HC7cU1hZuu8ZUfYnoDTpwOvX17PM_At8-fvq4v0OXVl816dYk043JA0tDl0lS2FlRi5xwWhRRCCaKcNJYSXdVKOK1qsywqoZSkTrhqqXTFsFWVZWdgeujdpfh9b_uhbPP_2RB0Z-O-L6mQRNICE5Wt_GA1KfZ9sq7c5YV1GkuCy78Ey0ywfCJYHgnm2PvjhH2VtefQE7JswAfDv3jcpy4v_P_OP5DxqcI</recordid><startdate>20211028</startdate><enddate>20211028</enddate><creator>Czako, Barbara</creator><creator>Sun, Yuting</creator><creator>McAfoos, Timothy</creator><creator>Cross, Jason B</creator><creator>Leonard, Paul G</creator><creator>Burke, Jason P</creator><creator>Carroll, Christopher L</creator><creator>Feng, Ningping</creator><creator>Harris, Angela L</creator><creator>Jiang, Yongying</creator><creator>Kang, Zhijun</creator><creator>Kovacs, Jeffrey J</creator><creator>Mandal, Pijus</creator><creator>Meyers, Brooke A</creator><creator>Mseeh, Faika</creator><creator>Parker, Connor A</creator><creator>Yu, Simon S</creator><creator>Williams, Christopher C</creator><creator>Wu, Qi</creator><creator>Di Francesco, Maria Emilia</creator><creator>Draetta, Giulio</creator><creator>Heffernan, Timothy</creator><creator>Marszalek, Joseph. R</creator><creator>Kohl, Nancy E</creator><creator>Jones, Philip</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>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-3357-7514</orcidid></search><sort><creationdate>20211028</creationdate><title>Discovery of 6‑[(3S,4S)‑4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor</title><author>Czako, Barbara ; Sun, Yuting ; McAfoos, Timothy ; Cross, Jason B ; Leonard, Paul G ; Burke, Jason P ; Carroll, Christopher L ; Feng, Ningping ; Harris, Angela L ; Jiang, Yongying ; Kang, Zhijun ; Kovacs, Jeffrey J ; Mandal, Pijus ; Meyers, Brooke A ; Mseeh, Faika ; Parker, Connor A ; Yu, Simon S ; Williams, Christopher C ; Wu, Qi ; Di Francesco, Maria Emilia ; Draetta, Giulio ; Heffernan, Timothy ; Marszalek, Joseph. R ; Kohl, Nancy E ; Jones, Philip</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-8c277cbed5280fff0568559519f8ce21abd95fa9dc76b59982f5fb79ab30e9be3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Enzyme Inhibitors - administration & dosage</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - metabolism</topic><topic>Neoplasms, Experimental - pathology</topic><topic>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors</topic><topic>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Czako, Barbara</creatorcontrib><creatorcontrib>Sun, Yuting</creatorcontrib><creatorcontrib>McAfoos, Timothy</creatorcontrib><creatorcontrib>Cross, Jason B</creatorcontrib><creatorcontrib>Leonard, Paul G</creatorcontrib><creatorcontrib>Burke, Jason P</creatorcontrib><creatorcontrib>Carroll, Christopher L</creatorcontrib><creatorcontrib>Feng, Ningping</creatorcontrib><creatorcontrib>Harris, Angela L</creatorcontrib><creatorcontrib>Jiang, Yongying</creatorcontrib><creatorcontrib>Kang, Zhijun</creatorcontrib><creatorcontrib>Kovacs, Jeffrey J</creatorcontrib><creatorcontrib>Mandal, Pijus</creatorcontrib><creatorcontrib>Meyers, Brooke A</creatorcontrib><creatorcontrib>Mseeh, Faika</creatorcontrib><creatorcontrib>Parker, Connor A</creatorcontrib><creatorcontrib>Yu, Simon S</creatorcontrib><creatorcontrib>Williams, Christopher C</creatorcontrib><creatorcontrib>Wu, Qi</creatorcontrib><creatorcontrib>Di Francesco, Maria Emilia</creatorcontrib><creatorcontrib>Draetta, Giulio</creatorcontrib><creatorcontrib>Heffernan, Timothy</creatorcontrib><creatorcontrib>Marszalek, Joseph. R</creatorcontrib><creatorcontrib>Kohl, Nancy E</creatorcontrib><creatorcontrib>Jones, Philip</creatorcontrib><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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Czako, Barbara</au><au>Sun, Yuting</au><au>McAfoos, Timothy</au><au>Cross, Jason B</au><au>Leonard, Paul G</au><au>Burke, Jason P</au><au>Carroll, Christopher L</au><au>Feng, Ningping</au><au>Harris, Angela L</au><au>Jiang, Yongying</au><au>Kang, Zhijun</au><au>Kovacs, Jeffrey J</au><au>Mandal, Pijus</au><au>Meyers, Brooke A</au><au>Mseeh, Faika</au><au>Parker, Connor A</au><au>Yu, Simon S</au><au>Williams, Christopher C</au><au>Wu, Qi</au><au>Di Francesco, Maria Emilia</au><au>Draetta, Giulio</au><au>Heffernan, Timothy</au><au>Marszalek, Joseph. R</au><au>Kohl, Nancy E</au><au>Jones, Philip</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of 6‑[(3S,4S)‑4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2021-10-28</date><risdate>2021</risdate><volume>64</volume><issue>20</issue><spage>15141</spage><epage>15169</epage><pages>15141-15169</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>34643390</pmid><doi>10.1021/acs.jmedchem.1c01132</doi><tpages>29</tpages><orcidid>https://orcid.org/0000-0002-3357-7514</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2021-10, Vol.64 (20), p.15141-15169 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2581826019 |
| source | ACS Publications; MEDLINE |
| subjects | Administration, Oral Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line, Tumor Cell Proliferation - drug effects Dose-Response Relationship, Drug Drug Discovery Drug Screening Assays, Antitumor Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Mice Molecular Structure Neoplasms, Experimental - drug therapy Neoplasms, Experimental - metabolism Neoplasms, Experimental - pathology Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism Structure-Activity Relationship |
| title | Discovery of 6‑[(3S,4S)‑4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-15T17%3A52%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%206%E2%80%91%5B(3S,4S)%E2%80%914-Amino-3-methyl-2-oxa-8-azaspiro%5B4.5%5Ddecan-8-yl%5D-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one%20(IACS-15414),%20a%20Potent%20and%20Orally%20Bioavailable%20SHP2%20Inhibitor&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Czako,%20Barbara&rft.date=2021-10-28&rft.volume=64&rft.issue=20&rft.spage=15141&rft.epage=15169&rft.pages=15141-15169&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.1c01132&rft_dat=%3Cproquest_cross%3E2581826019%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2581826019&rft_id=info:pmid/34643390&rfr_iscdi=true |