Novel allosteric glutaminase 1 inhibitors with macrocyclic structure activity relationship analysis
[Display omitted] Glutamine-addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co-occurring mutations. Selective glutaminase1 (GLS1) inhibition was reported using BPTES which has novel mode of allosteric inhibition. However, BPTES is a highly hydro...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2022-11, Vol.75, p.128956-128956, Article 128956 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Lee, Eun Ji Duggirala, Krishna Babu Lee, Yujin Yun, Mi Ran Jang, Jiyoon Cyriac, Rajath Jung, Myoung Eun Choi, Gildon Chae, Chong Hak Cho, Byoung Chul Lee, Kwangho |
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Glutamine-addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co-occurring mutations. Selective glutaminase1 (GLS1) inhibition was reported using BPTES which has novel mode of allosteric inhibition. However, BPTES is a highly hydrophobic and symmetric molecule with very poor solubility which results in suboptimal pharmacokinetic parameters and hinders its further development. As an ongoing effort to identify more drug-like GLS1 inhibitors via systematic structure − activity relationship (SAR) analysis of BPTES analogs, we disclose our novel macrocycles for GLS1 inhibition with conclusive SAR analysis on the core, core linker, and wing linker, respectively. Selected molecules resulted in reduction in intracellular glutamate levels in LR (LDK378-resistant) cells which is consistent to cell viability result. Finally, compounds 13 selectively reduced the growth of A549 and H460 cells which have co-occurring mutations including KRAS and KEAP1. |
| doi_str_mv | 10.1016/j.bmcl.2022.128956 |
| format | Article |
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Glutamine-addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co-occurring mutations. Selective glutaminase1 (GLS1) inhibition was reported using BPTES which has novel mode of allosteric inhibition. However, BPTES is a highly hydrophobic and symmetric molecule with very poor solubility which results in suboptimal pharmacokinetic parameters and hinders its further development. As an ongoing effort to identify more drug-like GLS1 inhibitors via systematic structure − activity relationship (SAR) analysis of BPTES analogs, we disclose our novel macrocycles for GLS1 inhibition with conclusive SAR analysis on the core, core linker, and wing linker, respectively. Selected molecules resulted in reduction in intracellular glutamate levels in LR (LDK378-resistant) cells which is consistent to cell viability result. Finally, compounds 13 selectively reduced the growth of A549 and H460 cells which have co-occurring mutations including KRAS and KEAP1.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2022.128956</identifier><language>eng</language><publisher>Elsevier Ltd</publisher><subject>Anticancer ; BPTES ; Cancer metabolism ; GLS1 ; Glutaminase 1 ; KEAP1 ; KRAS ; Macrocycle</subject><ispartof>Bioorganic & medicinal chemistry letters, 2022-11, Vol.75, p.128956-128956, Article 128956</ispartof><rights>2022 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c377t-fb691a33ab84df7e47541eb23085bc38cc386bfcac4e7cfc8f22baed5d2178703</citedby><cites>FETCH-LOGICAL-c377t-fb691a33ab84df7e47541eb23085bc38cc386bfcac4e7cfc8f22baed5d2178703</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2022.128956$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids></links><search><creatorcontrib>Lee, Eun Ji</creatorcontrib><creatorcontrib>Duggirala, Krishna Babu</creatorcontrib><creatorcontrib>Lee, Yujin</creatorcontrib><creatorcontrib>Yun, Mi Ran</creatorcontrib><creatorcontrib>Jang, Jiyoon</creatorcontrib><creatorcontrib>Cyriac, Rajath</creatorcontrib><creatorcontrib>Jung, Myoung Eun</creatorcontrib><creatorcontrib>Choi, Gildon</creatorcontrib><creatorcontrib>Chae, Chong Hak</creatorcontrib><creatorcontrib>Cho, Byoung Chul</creatorcontrib><creatorcontrib>Lee, Kwangho</creatorcontrib><title>Novel allosteric glutaminase 1 inhibitors with macrocyclic structure activity relationship analysis</title><title>Bioorganic & medicinal chemistry letters</title><description>[Display omitted]
Glutamine-addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co-occurring mutations. Selective glutaminase1 (GLS1) inhibition was reported using BPTES which has novel mode of allosteric inhibition. However, BPTES is a highly hydrophobic and symmetric molecule with very poor solubility which results in suboptimal pharmacokinetic parameters and hinders its further development. As an ongoing effort to identify more drug-like GLS1 inhibitors via systematic structure − activity relationship (SAR) analysis of BPTES analogs, we disclose our novel macrocycles for GLS1 inhibition with conclusive SAR analysis on the core, core linker, and wing linker, respectively. Selected molecules resulted in reduction in intracellular glutamate levels in LR (LDK378-resistant) cells which is consistent to cell viability result. Finally, compounds 13 selectively reduced the growth of A549 and H460 cells which have co-occurring mutations including KRAS and KEAP1.</description><subject>Anticancer</subject><subject>BPTES</subject><subject>Cancer metabolism</subject><subject>GLS1</subject><subject>Glutaminase 1</subject><subject>KEAP1</subject><subject>KRAS</subject><subject>Macrocycle</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kMtOwzAQRS0EEqXwA6y8ZJNiO85LYoMqXlIFG5DYWc5kQqdykmI7Rf17UpU1i9Fs7rnSPYxdS7GQQua3m0XdgVsoodRCqrLK8hM2kzrXSapFdspmospFUlb685xdhLARQmqh9YzB67BDx61zQ4joCfiXG6PtqLcBueTUr6mmOPjAfyiueWfBD7AHNyVD9CPE0SO3EGlHcc89Ohtp6MOattz21u0DhUt21loX8Orvz9nH48P78jlZvT29LO9XCaRFEZO2zitp09TWpW7aAnWRaYm1SkWZ1ZCWMF1et2BBYwEtlK1StcUma5QsykKkc3Zz7N364XvEEE1HAdA52-MwBqMKUaqsSrWaouoYndaE4LE1W0-d9XsjhTkYNRtzMGoORs3R6ATdHSGcRuwIvQlA2AM25BGiaQb6D_8F5_uCoQ</recordid><startdate>20221101</startdate><enddate>20221101</enddate><creator>Lee, Eun Ji</creator><creator>Duggirala, Krishna Babu</creator><creator>Lee, Yujin</creator><creator>Yun, Mi Ran</creator><creator>Jang, Jiyoon</creator><creator>Cyriac, Rajath</creator><creator>Jung, Myoung Eun</creator><creator>Choi, Gildon</creator><creator>Chae, Chong Hak</creator><creator>Cho, Byoung Chul</creator><creator>Lee, Kwangho</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20221101</creationdate><title>Novel allosteric glutaminase 1 inhibitors with macrocyclic structure activity relationship analysis</title><author>Lee, Eun Ji ; Duggirala, Krishna Babu ; Lee, Yujin ; Yun, Mi Ran ; Jang, Jiyoon ; Cyriac, Rajath ; Jung, Myoung Eun ; Choi, Gildon ; Chae, Chong Hak ; Cho, Byoung Chul ; Lee, Kwangho</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c377t-fb691a33ab84df7e47541eb23085bc38cc386bfcac4e7cfc8f22baed5d2178703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Anticancer</topic><topic>BPTES</topic><topic>Cancer metabolism</topic><topic>GLS1</topic><topic>Glutaminase 1</topic><topic>KEAP1</topic><topic>KRAS</topic><topic>Macrocycle</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Eun Ji</creatorcontrib><creatorcontrib>Duggirala, Krishna Babu</creatorcontrib><creatorcontrib>Lee, Yujin</creatorcontrib><creatorcontrib>Yun, Mi Ran</creatorcontrib><creatorcontrib>Jang, Jiyoon</creatorcontrib><creatorcontrib>Cyriac, Rajath</creatorcontrib><creatorcontrib>Jung, Myoung Eun</creatorcontrib><creatorcontrib>Choi, Gildon</creatorcontrib><creatorcontrib>Chae, Chong Hak</creatorcontrib><creatorcontrib>Cho, Byoung Chul</creatorcontrib><creatorcontrib>Lee, Kwangho</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Eun Ji</au><au>Duggirala, Krishna Babu</au><au>Lee, Yujin</au><au>Yun, Mi Ran</au><au>Jang, Jiyoon</au><au>Cyriac, Rajath</au><au>Jung, Myoung Eun</au><au>Choi, Gildon</au><au>Chae, Chong Hak</au><au>Cho, Byoung Chul</au><au>Lee, Kwangho</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel allosteric glutaminase 1 inhibitors with macrocyclic structure activity relationship analysis</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><date>2022-11-01</date><risdate>2022</risdate><volume>75</volume><spage>128956</spage><epage>128956</epage><pages>128956-128956</pages><artnum>128956</artnum><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Glutamine-addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co-occurring mutations. Selective glutaminase1 (GLS1) inhibition was reported using BPTES which has novel mode of allosteric inhibition. However, BPTES is a highly hydrophobic and symmetric molecule with very poor solubility which results in suboptimal pharmacokinetic parameters and hinders its further development. As an ongoing effort to identify more drug-like GLS1 inhibitors via systematic structure − activity relationship (SAR) analysis of BPTES analogs, we disclose our novel macrocycles for GLS1 inhibition with conclusive SAR analysis on the core, core linker, and wing linker, respectively. Selected molecules resulted in reduction in intracellular glutamate levels in LR (LDK378-resistant) cells which is consistent to cell viability result. Finally, compounds 13 selectively reduced the growth of A549 and H460 cells which have co-occurring mutations including KRAS and KEAP1.</abstract><pub>Elsevier Ltd</pub><doi>10.1016/j.bmcl.2022.128956</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Anticancer BPTES Cancer metabolism GLS1 Glutaminase 1 KEAP1 KRAS Macrocycle |
| title | Novel allosteric glutaminase 1 inhibitors with macrocyclic structure activity relationship analysis |
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