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KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma
Purpose A major challenge to developing new therapies for patients with malignant brain tumors is that relatively few small molecule anticancer drugs penetrate the blood–brain barrier (BBB) well enough to provide therapeutically effective concentrations in brain tissue before drug exposure in non-CN...
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| Published in: | Journal of neuro-oncology 2018-12, Vol.140 (3), p.519-527 |
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| Main Authors: | , , , , , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-c372t-b683fe6bcc243daeb03d7c623b3c9633f19f4033be34780c34f08888628117a3 |
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| cites | cdi_FETCH-LOGICAL-c372t-b683fe6bcc243daeb03d7c623b3c9633f19f4033be34780c34f08888628117a3 |
| container_end_page | 527 |
| container_issue | 3 |
| container_start_page | 519 |
| container_title | Journal of neuro-oncology |
| container_volume | 140 |
| creator | Ciesielski, Michael J. Bu, Yahao Munich, Stephan A. Teegarden, Paola Smolinski, Michael P. Clements, James L. Lau, Johnson Y. N. Hangauer, David G. Fenstermaker, Robert A. |
| description | Purpose
A major challenge to developing new therapies for patients with malignant brain tumors is that relatively few small molecule anticancer drugs penetrate the blood–brain barrier (BBB) well enough to provide therapeutically effective concentrations in brain tissue before drug exposure in non-CNS tissues results in unacceptable toxicity.
Methods
KX2-361, a member of a novel family of compounds with Src-kinase and tubulin polymerization inhibitory activity, demonstrates good oral bioavailability and readily crosses the BBB in mice. The objective of this study was to investigate the activity of KX2-361 against human and murine glioma cells and assess its therapeutic effect in a syngeneic orthotopic model of glioblastoma.
Results
In addition to reducing the level of Src autophosphorylation in the GL261 murine glioblastoma cell line, KX2-361 binds directly to tubulin and disrupts microtubule architecture in glioma cells maintained in culture.
Conclusions
The drug is active in vivo against orthotopic GL261 gliomas in syngeneic C57BL/6 mice. Long term survival is not observed in mice lacking an adaptive immune system, indicating that KX2-361 works in concert with the host immune system to control tumor growth and promote long-term survival in the GL261 glioma model. |
| doi_str_mv | 10.1007/s11060-018-2992-4 |
| format | article |
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A major challenge to developing new therapies for patients with malignant brain tumors is that relatively few small molecule anticancer drugs penetrate the blood–brain barrier (BBB) well enough to provide therapeutically effective concentrations in brain tissue before drug exposure in non-CNS tissues results in unacceptable toxicity.
Methods
KX2-361, a member of a novel family of compounds with Src-kinase and tubulin polymerization inhibitory activity, demonstrates good oral bioavailability and readily crosses the BBB in mice. The objective of this study was to investigate the activity of KX2-361 against human and murine glioma cells and assess its therapeutic effect in a syngeneic orthotopic model of glioblastoma.
Results
In addition to reducing the level of Src autophosphorylation in the GL261 murine glioblastoma cell line, KX2-361 binds directly to tubulin and disrupts microtubule architecture in glioma cells maintained in culture.
Conclusions
The drug is active in vivo against orthotopic GL261 gliomas in syngeneic C57BL/6 mice. Long term survival is not observed in mice lacking an adaptive immune system, indicating that KX2-361 works in concert with the host immune system to control tumor growth and promote long-term survival in the GL261 glioma model.</description><identifier>ISSN: 0167-594X</identifier><identifier>EISSN: 1573-7373</identifier><identifier>DOI: 10.1007/s11060-018-2992-4</identifier><identifier>PMID: 30238350</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject><![CDATA[Acetamides - administration & dosage ; Animal models ; Animals ; Antineoplastic Agents - administration & dosage ; Antineoplastic drugs ; Antitumor agents ; Apoptosis ; Bioavailability ; Blood-brain barrier ; Blood-Brain Barrier - metabolism ; Brain cancer ; Brain Neoplasms - drug therapy ; Brain Neoplasms - metabolism ; Brain tumors ; Cell culture ; Cell Cycle Checkpoints ; Cell Line, Tumor ; Central nervous system ; Disease Models, Animal ; Glioblastoma ; Glioblastoma - drug therapy ; Glioblastoma - metabolism ; Glioma cells ; Humans ; Immune system ; Immunosuppressive agents ; Laboratory Investigation ; Medicine ; Medicine & Public Health ; Mice, Inbred C57BL ; Morpholines - administration & dosage ; Neurology ; Oncology ; Phosphorylation ; Polymerization ; Protein Kinase Inhibitors - administration & dosage ; Pyridines - administration & dosage ; src-Family Kinases - antagonists & inhibitors ; Toxicity ; Tubulin ; Tubulin Modulators - administration & dosage]]></subject><ispartof>Journal of neuro-oncology, 2018-12, Vol.140 (3), p.519-527</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2018</rights><rights>Journal of Neuro-Oncology is a copyright of Springer, (2018). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-b683fe6bcc243daeb03d7c623b3c9633f19f4033be34780c34f08888628117a3</citedby><cites>FETCH-LOGICAL-c372t-b683fe6bcc243daeb03d7c623b3c9633f19f4033be34780c34f08888628117a3</cites></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/30238350$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ciesielski, Michael J.</creatorcontrib><creatorcontrib>Bu, Yahao</creatorcontrib><creatorcontrib>Munich, Stephan A.</creatorcontrib><creatorcontrib>Teegarden, Paola</creatorcontrib><creatorcontrib>Smolinski, Michael P.</creatorcontrib><creatorcontrib>Clements, James L.</creatorcontrib><creatorcontrib>Lau, Johnson Y. N.</creatorcontrib><creatorcontrib>Hangauer, David G.</creatorcontrib><creatorcontrib>Fenstermaker, Robert A.</creatorcontrib><title>KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma</title><title>Journal of neuro-oncology</title><addtitle>J Neurooncol</addtitle><addtitle>J Neurooncol</addtitle><description>Purpose
A major challenge to developing new therapies for patients with malignant brain tumors is that relatively few small molecule anticancer drugs penetrate the blood–brain barrier (BBB) well enough to provide therapeutically effective concentrations in brain tissue before drug exposure in non-CNS tissues results in unacceptable toxicity.
Methods
KX2-361, a member of a novel family of compounds with Src-kinase and tubulin polymerization inhibitory activity, demonstrates good oral bioavailability and readily crosses the BBB in mice. The objective of this study was to investigate the activity of KX2-361 against human and murine glioma cells and assess its therapeutic effect in a syngeneic orthotopic model of glioblastoma.
Results
In addition to reducing the level of Src autophosphorylation in the GL261 murine glioblastoma cell line, KX2-361 binds directly to tubulin and disrupts microtubule architecture in glioma cells maintained in culture.
Conclusions
The drug is active in vivo against orthotopic GL261 gliomas in syngeneic C57BL/6 mice. Long term survival is not observed in mice lacking an adaptive immune system, indicating that KX2-361 works in concert with the host immune system to control tumor growth and promote long-term survival in the GL261 glioma model.</description><subject>Acetamides - administration & dosage</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic drugs</subject><subject>Antitumor agents</subject><subject>Apoptosis</subject><subject>Bioavailability</subject><subject>Blood-brain barrier</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Brain cancer</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain tumors</subject><subject>Cell culture</subject><subject>Cell Cycle Checkpoints</subject><subject>Cell Line, Tumor</subject><subject>Central nervous system</subject><subject>Disease Models, Animal</subject><subject>Glioblastoma</subject><subject>Glioblastoma - drug therapy</subject><subject>Glioblastoma - metabolism</subject><subject>Glioma cells</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunosuppressive agents</subject><subject>Laboratory Investigation</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice, Inbred C57BL</subject><subject>Morpholines - administration & dosage</subject><subject>Neurology</subject><subject>Oncology</subject><subject>Phosphorylation</subject><subject>Polymerization</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Pyridines - administration & dosage</subject><subject>src-Family Kinases - antagonists & inhibitors</subject><subject>Toxicity</subject><subject>Tubulin</subject><subject>Tubulin Modulators - administration & dosage</subject><issn>0167-594X</issn><issn>1573-7373</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kUFvFSEUhYnR2NfqD3BjSFzTXrjzhhl3plHbtEkXdtEdAYZ5pWGGCsMk_Rn9x_Lyqq7KhgDfOYfcQ8gnDqccQJ5lzqEFBrxjou8Fa96QDd9KZBIlviUb4K1k2765OyLHOT8AQCORvydHCAI73MKGPF_dCYYt_0o1nePqAo1Jh_BEjY961T5oExzNU72jUwzOlnocig70V7JnSzEl-Jn6-d4bv8REl3u90McUVz-4TEOcd3RxaaK5pNWvVVZpTaeS_Oyq4bAPHOku-GiCzkuc9AfybtQhu48v-wm5_fH99vyCXd_8vDz_ds0sSrEw03Y4utZYKxoctDOAg7StQIO2bxFH3o8NIBqHjezAYjNCV1crOs6lxhPy5WBbP_u7uLyoh1jSXBOVqGPlIKHHSvEDZVPMOblRPSY_6fSkOKh9B-rQgaodqH0Hqqmazy_OxUxu-Kf4O_QKiAOQ69O8c-l_9OuufwCU2JKG</recordid><startdate>20181201</startdate><enddate>20181201</enddate><creator>Ciesielski, Michael J.</creator><creator>Bu, Yahao</creator><creator>Munich, Stephan A.</creator><creator>Teegarden, Paola</creator><creator>Smolinski, Michael P.</creator><creator>Clements, James L.</creator><creator>Lau, Johnson Y. N.</creator><creator>Hangauer, David G.</creator><creator>Fenstermaker, Robert A.</creator><general>Springer US</general><general>Springer Nature B.V</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>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20181201</creationdate><title>KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma</title><author>Ciesielski, Michael J. ; Bu, Yahao ; Munich, Stephan A. ; Teegarden, Paola ; Smolinski, Michael P. ; Clements, James L. ; Lau, Johnson Y. N. ; Hangauer, David G. ; Fenstermaker, Robert A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c372t-b683fe6bcc243daeb03d7c623b3c9633f19f4033be34780c34f08888628117a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Acetamides - administration & dosage</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic drugs</topic><topic>Antitumor agents</topic><topic>Apoptosis</topic><topic>Bioavailability</topic><topic>Blood-brain barrier</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Brain cancer</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Brain Neoplasms - metabolism</topic><topic>Brain tumors</topic><topic>Cell culture</topic><topic>Cell Cycle Checkpoints</topic><topic>Cell Line, Tumor</topic><topic>Central nervous system</topic><topic>Disease Models, Animal</topic><topic>Glioblastoma</topic><topic>Glioblastoma - drug therapy</topic><topic>Glioblastoma - metabolism</topic><topic>Glioma cells</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immunosuppressive agents</topic><topic>Laboratory Investigation</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice, Inbred C57BL</topic><topic>Morpholines - administration & dosage</topic><topic>Neurology</topic><topic>Oncology</topic><topic>Phosphorylation</topic><topic>Polymerization</topic><topic>Protein Kinase Inhibitors - administration & dosage</topic><topic>Pyridines - administration & dosage</topic><topic>src-Family Kinases - antagonists & inhibitors</topic><topic>Toxicity</topic><topic>Tubulin</topic><topic>Tubulin Modulators - administration & dosage</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ciesielski, Michael J.</creatorcontrib><creatorcontrib>Bu, Yahao</creatorcontrib><creatorcontrib>Munich, Stephan A.</creatorcontrib><creatorcontrib>Teegarden, Paola</creatorcontrib><creatorcontrib>Smolinski, Michael P.</creatorcontrib><creatorcontrib>Clements, James L.</creatorcontrib><creatorcontrib>Lau, Johnson Y. N.</creatorcontrib><creatorcontrib>Hangauer, David G.</creatorcontrib><creatorcontrib>Fenstermaker, Robert A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection (ProQuest Medical & Health Databases)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database (ProQuest Medical & Health Databases)</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)</collection><collection>ProQuest Central</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</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><jtitle>Journal of neuro-oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ciesielski, Michael J.</au><au>Bu, Yahao</au><au>Munich, Stephan A.</au><au>Teegarden, Paola</au><au>Smolinski, Michael P.</au><au>Clements, James L.</au><au>Lau, Johnson Y. N.</au><au>Hangauer, David G.</au><au>Fenstermaker, Robert A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma</atitle><jtitle>Journal of neuro-oncology</jtitle><stitle>J Neurooncol</stitle><addtitle>J Neurooncol</addtitle><date>2018-12-01</date><risdate>2018</risdate><volume>140</volume><issue>3</issue><spage>519</spage><epage>527</epage><pages>519-527</pages><issn>0167-594X</issn><eissn>1573-7373</eissn><abstract>Purpose
A major challenge to developing new therapies for patients with malignant brain tumors is that relatively few small molecule anticancer drugs penetrate the blood–brain barrier (BBB) well enough to provide therapeutically effective concentrations in brain tissue before drug exposure in non-CNS tissues results in unacceptable toxicity.
Methods
KX2-361, a member of a novel family of compounds with Src-kinase and tubulin polymerization inhibitory activity, demonstrates good oral bioavailability and readily crosses the BBB in mice. The objective of this study was to investigate the activity of KX2-361 against human and murine glioma cells and assess its therapeutic effect in a syngeneic orthotopic model of glioblastoma.
Results
In addition to reducing the level of Src autophosphorylation in the GL261 murine glioblastoma cell line, KX2-361 binds directly to tubulin and disrupts microtubule architecture in glioma cells maintained in culture.
Conclusions
The drug is active in vivo against orthotopic GL261 gliomas in syngeneic C57BL/6 mice. Long term survival is not observed in mice lacking an adaptive immune system, indicating that KX2-361 works in concert with the host immune system to control tumor growth and promote long-term survival in the GL261 glioma model.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>30238350</pmid><doi>10.1007/s11060-018-2992-4</doi><tpages>9</tpages></addata></record> |
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| ispartof | Journal of neuro-oncology, 2018-12, Vol.140 (3), p.519-527 |
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| subjects | Acetamides - administration & dosage Animal models Animals Antineoplastic Agents - administration & dosage Antineoplastic drugs Antitumor agents Apoptosis Bioavailability Blood-brain barrier Blood-Brain Barrier - metabolism Brain cancer Brain Neoplasms - drug therapy Brain Neoplasms - metabolism Brain tumors Cell culture Cell Cycle Checkpoints Cell Line, Tumor Central nervous system Disease Models, Animal Glioblastoma Glioblastoma - drug therapy Glioblastoma - metabolism Glioma cells Humans Immune system Immunosuppressive agents Laboratory Investigation Medicine Medicine & Public Health Mice, Inbred C57BL Morpholines - administration & dosage Neurology Oncology Phosphorylation Polymerization Protein Kinase Inhibitors - administration & dosage Pyridines - administration & dosage src-Family Kinases - antagonists & inhibitors Toxicity Tubulin Tubulin Modulators - administration & dosage |
| title | KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma |
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