Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties
The UNC-51-like kinase-1 (ULK1) is one of the central upstream regulators of the autophagy pathway, represents a key target for the development of molecular probes to abrogate autophagy and explore potential therapeutic avenues. Here we report the discovery, structure-activity and structure-property...
Gespeichert in:
| Veröffentlicht in: | European journal of medicinal chemistry 2023-12, Vol.266, p.116101 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | |
| container_start_page | 116101 |
| container_title | European journal of medicinal chemistry |
| container_volume | 266 |
| creator | Morozova, Alisa Chan, Sean Chin Bayle, Simon Sun, Luxin Grassie, Dylan Iermolaieva, Anna Kalaga, Mahalakshmi N Frydman, Sylvia Sansil, Samer Schönbrunn, Ernst Duckett, Derek Monastyrskyi, Andrii |
| description | The UNC-51-like kinase-1 (ULK1) is one of the central upstream regulators of the autophagy pathway, represents a key target for the development of molecular probes to abrogate autophagy and explore potential therapeutic avenues. Here we report the discovery, structure-activity and structure-property relationships of selective, potent, and cell-active ULK1/2 inhibitors based on a 7-azaindole scaffold. Using structure-based drug design, we have developed a series of analogs with excellent binding affinity and biochemical activity against ULK1/2 (IC
|
| format | Article |
| fullrecord | <record><control><sourceid>pubmed</sourceid><recordid>TN_cdi_pubmed_primary_38232465</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>38232465</sourcerecordid><originalsourceid>FETCH-pubmed_primary_382324653</originalsourceid><addsrcrecordid>eNqFjs1qAjEURoNQqv15BbkvMDTOOKN7fxDaZbuWO-YGb8nkhiRG9Om10K67-g6Hs_hGajJbdMuqqdv5WD2l9K21bjutH9W4WdZNPe_aiTqtqZCTMJDPIBaC5B9CbyCRo0PmQvD18T57q4H9kXvOEhP0mMiAeFhUeEX2RhxBOqC14gycOR_BYpGI_d2zh8JFIEQJFDNTelEPFl2i1999VtPt5nO1q8KpH8jsQ-QB42X_97P5N7gBJ59JuA</addsrcrecordid><sourcetype>Index Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties</title><source>ScienceDirect Journals (5 years ago - present)</source><creator>Morozova, Alisa ; Chan, Sean Chin ; Bayle, Simon ; Sun, Luxin ; Grassie, Dylan ; Iermolaieva, Anna ; Kalaga, Mahalakshmi N ; Frydman, Sylvia ; Sansil, Samer ; Schönbrunn, Ernst ; Duckett, Derek ; Monastyrskyi, Andrii</creator><creatorcontrib>Morozova, Alisa ; Chan, Sean Chin ; Bayle, Simon ; Sun, Luxin ; Grassie, Dylan ; Iermolaieva, Anna ; Kalaga, Mahalakshmi N ; Frydman, Sylvia ; Sansil, Samer ; Schönbrunn, Ernst ; Duckett, Derek ; Monastyrskyi, Andrii</creatorcontrib><description>The UNC-51-like kinase-1 (ULK1) is one of the central upstream regulators of the autophagy pathway, represents a key target for the development of molecular probes to abrogate autophagy and explore potential therapeutic avenues. Here we report the discovery, structure-activity and structure-property relationships of selective, potent, and cell-active ULK1/2 inhibitors based on a 7-azaindole scaffold. Using structure-based drug design, we have developed a series of analogs with excellent binding affinity and biochemical activity against ULK1/2 (IC
< 25 nM). The validation of cellular target engagement for these compounds was achieved through the employment of the ULK1 NanoBRET intracellular kinase assay. Notably, we have successfully solved the crystal structure of the lead compound, MR-2088, bound to the active site of ULK1. Moreover, the combination treatment of MR-2088 with known KRAS→RAF→MEK→ERK pathway inhibitors, such as trametinib, showed promising synergistic effect in vitro using H2030 (KRAS
) cell lines. Lastly, our findings underscore MR-2088's potential to inhibit starvation/stimuli-induced autophagic flux, coupled with its suitability for in vivo studies based on its pharmacokinetic properties.</description><identifier>EISSN: 1768-3254</identifier><identifier>PMID: 38232465</identifier><language>eng</language><publisher>France</publisher><ispartof>European journal of medicinal chemistry, 2023-12, Vol.266, p.116101</ispartof><rights>Copyright © 2024 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38232465$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Morozova, Alisa</creatorcontrib><creatorcontrib>Chan, Sean Chin</creatorcontrib><creatorcontrib>Bayle, Simon</creatorcontrib><creatorcontrib>Sun, Luxin</creatorcontrib><creatorcontrib>Grassie, Dylan</creatorcontrib><creatorcontrib>Iermolaieva, Anna</creatorcontrib><creatorcontrib>Kalaga, Mahalakshmi N</creatorcontrib><creatorcontrib>Frydman, Sylvia</creatorcontrib><creatorcontrib>Sansil, Samer</creatorcontrib><creatorcontrib>Schönbrunn, Ernst</creatorcontrib><creatorcontrib>Duckett, Derek</creatorcontrib><creatorcontrib>Monastyrskyi, Andrii</creatorcontrib><title>Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>The UNC-51-like kinase-1 (ULK1) is one of the central upstream regulators of the autophagy pathway, represents a key target for the development of molecular probes to abrogate autophagy and explore potential therapeutic avenues. Here we report the discovery, structure-activity and structure-property relationships of selective, potent, and cell-active ULK1/2 inhibitors based on a 7-azaindole scaffold. Using structure-based drug design, we have developed a series of analogs with excellent binding affinity and biochemical activity against ULK1/2 (IC
< 25 nM). The validation of cellular target engagement for these compounds was achieved through the employment of the ULK1 NanoBRET intracellular kinase assay. Notably, we have successfully solved the crystal structure of the lead compound, MR-2088, bound to the active site of ULK1. Moreover, the combination treatment of MR-2088 with known KRAS→RAF→MEK→ERK pathway inhibitors, such as trametinib, showed promising synergistic effect in vitro using H2030 (KRAS
) cell lines. Lastly, our findings underscore MR-2088's potential to inhibit starvation/stimuli-induced autophagic flux, coupled with its suitability for in vivo studies based on its pharmacokinetic properties.</description><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNqFjs1qAjEURoNQqv15BbkvMDTOOKN7fxDaZbuWO-YGb8nkhiRG9Om10K67-g6Hs_hGajJbdMuqqdv5WD2l9K21bjutH9W4WdZNPe_aiTqtqZCTMJDPIBaC5B9CbyCRo0PmQvD18T57q4H9kXvOEhP0mMiAeFhUeEX2RhxBOqC14gycOR_BYpGI_d2zh8JFIEQJFDNTelEPFl2i1999VtPt5nO1q8KpH8jsQ-QB42X_97P5N7gBJ59JuA</recordid><startdate>20231229</startdate><enddate>20231229</enddate><creator>Morozova, Alisa</creator><creator>Chan, Sean Chin</creator><creator>Bayle, Simon</creator><creator>Sun, Luxin</creator><creator>Grassie, Dylan</creator><creator>Iermolaieva, Anna</creator><creator>Kalaga, Mahalakshmi N</creator><creator>Frydman, Sylvia</creator><creator>Sansil, Samer</creator><creator>Schönbrunn, Ernst</creator><creator>Duckett, Derek</creator><creator>Monastyrskyi, Andrii</creator><scope>NPM</scope></search><sort><creationdate>20231229</creationdate><title>Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties</title><author>Morozova, Alisa ; Chan, Sean Chin ; Bayle, Simon ; Sun, Luxin ; Grassie, Dylan ; Iermolaieva, Anna ; Kalaga, Mahalakshmi N ; Frydman, Sylvia ; Sansil, Samer ; Schönbrunn, Ernst ; Duckett, Derek ; Monastyrskyi, Andrii</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_382324653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Morozova, Alisa</creatorcontrib><creatorcontrib>Chan, Sean Chin</creatorcontrib><creatorcontrib>Bayle, Simon</creatorcontrib><creatorcontrib>Sun, Luxin</creatorcontrib><creatorcontrib>Grassie, Dylan</creatorcontrib><creatorcontrib>Iermolaieva, Anna</creatorcontrib><creatorcontrib>Kalaga, Mahalakshmi N</creatorcontrib><creatorcontrib>Frydman, Sylvia</creatorcontrib><creatorcontrib>Sansil, Samer</creatorcontrib><creatorcontrib>Schönbrunn, Ernst</creatorcontrib><creatorcontrib>Duckett, Derek</creatorcontrib><creatorcontrib>Monastyrskyi, Andrii</creatorcontrib><collection>PubMed</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Morozova, Alisa</au><au>Chan, Sean Chin</au><au>Bayle, Simon</au><au>Sun, Luxin</au><au>Grassie, Dylan</au><au>Iermolaieva, Anna</au><au>Kalaga, Mahalakshmi N</au><au>Frydman, Sylvia</au><au>Sansil, Samer</au><au>Schönbrunn, Ernst</au><au>Duckett, Derek</au><au>Monastyrskyi, Andrii</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2023-12-29</date><risdate>2023</risdate><volume>266</volume><spage>116101</spage><pages>116101-</pages><eissn>1768-3254</eissn><abstract>The UNC-51-like kinase-1 (ULK1) is one of the central upstream regulators of the autophagy pathway, represents a key target for the development of molecular probes to abrogate autophagy and explore potential therapeutic avenues. Here we report the discovery, structure-activity and structure-property relationships of selective, potent, and cell-active ULK1/2 inhibitors based on a 7-azaindole scaffold. Using structure-based drug design, we have developed a series of analogs with excellent binding affinity and biochemical activity against ULK1/2 (IC
< 25 nM). The validation of cellular target engagement for these compounds was achieved through the employment of the ULK1 NanoBRET intracellular kinase assay. Notably, we have successfully solved the crystal structure of the lead compound, MR-2088, bound to the active site of ULK1. Moreover, the combination treatment of MR-2088 with known KRAS→RAF→MEK→ERK pathway inhibitors, such as trametinib, showed promising synergistic effect in vitro using H2030 (KRAS
) cell lines. Lastly, our findings underscore MR-2088's potential to inhibit starvation/stimuli-induced autophagic flux, coupled with its suitability for in vivo studies based on its pharmacokinetic properties.</abstract><cop>France</cop><pmid>38232465</pmid></addata></record> |
| fulltext | fulltext |
| identifier | EISSN: 1768-3254 |
| ispartof | European journal of medicinal chemistry, 2023-12, Vol.266, p.116101 |
| issn | 1768-3254 |
| language | eng |
| recordid | cdi_pubmed_primary_38232465 |
| source | ScienceDirect Journals (5 years ago - present) |
| title | Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-07T13%3A28%3A39IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Development%20of%20potent%20and%20selective%20ULK1/2%20inhibitors%20based%20on%207-azaindole%20scaffold%20with%20favorable%20in%20vivo%20properties&rft.jtitle=European%20journal%20of%20medicinal%20chemistry&rft.au=Morozova,%20Alisa&rft.date=2023-12-29&rft.volume=266&rft.spage=116101&rft.pages=116101-&rft.eissn=1768-3254&rft_id=info:doi/&rft_dat=%3Cpubmed%3E38232465%3C/pubmed%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/38232465&rfr_iscdi=true |