Discovery of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl)acetates as potent Hsp90 inhibitors with selectivity over TRAP1.
Identifieur interne : 000553 ( Main/Exploration ); précédent : 000552; suivant : 000554Discovery of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl)acetates as potent Hsp90 inhibitors with selectivity over TRAP1.
Auteurs : Sejin Jung [Corée du Sud] ; Nam Gu Yoon [Corée du Sud] ; Sujae Yang [Corée du Sud] ; Darong Kim [Corée du Sud] ; Won Seok Lee [Corée du Sud] ; Ki Bum Hong [Corée du Sud] ; Changwook Lee [Corée du Sud] ; Byoung Heon Kang [Corée du Sud] ; Ji Hoon Lee [Corée du Sud] ; Soosung Kang [Corée du Sud]Source :
- Bioorganic & medicinal chemistry letters [ 1464-3405 ] ; 2020.
Abstract
As the most abundant heat shock protein (HSP), Hsp90 is actively involved in tumor cell growth and various responses to anti-carcinogenic stress. Hsp90 has thus emerged as a potential drug target. A structure-based drug design approach was applied to develop novel resorcinolyltriazole derivatives as Hsp90 inhibitors. Structure-activity relationships (SARs) and molecular docking were investigated to provide a rationale for binding affinity and paralog selectivity. Click chemistry between iodoethynylresorcinol and an azido derivative was used to synthesize a new family of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl) acetates that exhibited Hsp90 binding affinities of 40-100 nM (IC50). Among the synthesized molecules, the triazole alkyl acetates displayed the highest Hsp90 binding affinities. Their potency against Hsp90 was over 100-fold stronger than against TRAP1 and 1-3-fold stronger than against Grp94. In particular, compounds 18, 19, and 30 had Hsp90 inhibitory activities of ~45 nM (IC50) and they displayed over 350-fold selectivity for Hsp90 over TRAP1.
DOI: 10.1016/j.bmcl.2019.126809
PubMed: 31839539
Affiliations:
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Electronic address: kangbh@unist.ac.kr.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919</wicri:regionArea><wicri:noRegion>Ulsan 44919</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Ji Hoon" sort="Lee, Ji Hoon" uniqKey="Lee J" first="Ji Hoon" last="Lee">Ji Hoon Lee</name><affiliation wicri:level="1"><nlm:affiliation>New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea. Electronic address: jhlee@dgmif.re.kr.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061</wicri:regionArea><wicri:noRegion>Daegu 41061</wicri:noRegion></affiliation></author><author><name sortKey="Kang, Soosung" sort="Kang, Soosung" uniqKey="Kang S" first="Soosung" last="Kang">Soosung Kang</name><affiliation wicri:level="1"><nlm:affiliation>College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea; Western Seoul Center, Korea Basic Science Institute, Seoul 03760, South Korea. 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Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061</wicri:regionArea><wicri:noRegion>Daegu 41061</wicri:noRegion></affiliation></author><author><name sortKey="Yoon, Nam Gu" sort="Yoon, Nam Gu" uniqKey="Yoon N" first="Nam Gu" last="Yoon">Nam Gu Yoon</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919, South Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919</wicri:regionArea><wicri:noRegion>Ulsan 44919</wicri:noRegion></affiliation></author><author><name sortKey="Yang, Sujae" sort="Yang, Sujae" uniqKey="Yang S" first="Sujae" last="Yang">Sujae Yang</name><affiliation wicri:level="1"><nlm:affiliation>College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Kim, Darong" sort="Kim, Darong" uniqKey="Kim D" first="Darong" last="Kim">Darong Kim</name><affiliation wicri:level="1"><nlm:affiliation>New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061</wicri:regionArea><wicri:noRegion>Daegu 41061</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Won Seok" sort="Lee, Won Seok" uniqKey="Lee W" first="Won Seok" last="Lee">Won Seok Lee</name><affiliation wicri:level="1"><nlm:affiliation>New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061</wicri:regionArea><wicri:noRegion>Daegu 41061</wicri:noRegion></affiliation></author><author><name sortKey="Hong, Ki Bum" sort="Hong, Ki Bum" uniqKey="Hong K" first="Ki Bum" last="Hong">Ki Bum Hong</name><affiliation wicri:level="1"><nlm:affiliation>New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061</wicri:regionArea><wicri:noRegion>Daegu 41061</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Changwook" sort="Lee, Changwook" uniqKey="Lee C" first="Changwook" last="Lee">Changwook Lee</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919, South Korea.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919</wicri:regionArea><wicri:noRegion>Ulsan 44919</wicri:noRegion></affiliation></author><author><name sortKey="Kang, Byoung Heon" sort="Kang, Byoung Heon" uniqKey="Kang B" first="Byoung Heon" last="Kang">Byoung Heon Kang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919, South Korea. Electronic address: kangbh@unist.ac.kr.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919</wicri:regionArea><wicri:noRegion>Ulsan 44919</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Ji Hoon" sort="Lee, Ji Hoon" uniqKey="Lee J" first="Ji Hoon" last="Lee">Ji Hoon Lee</name><affiliation wicri:level="1"><nlm:affiliation>New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea. Electronic address: jhlee@dgmif.re.kr.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061</wicri:regionArea><wicri:noRegion>Daegu 41061</wicri:noRegion></affiliation></author><author><name sortKey="Kang, Soosung" sort="Kang, Soosung" uniqKey="Kang S" first="Soosung" last="Kang">Soosung Kang</name><affiliation wicri:level="1"><nlm:affiliation>College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea; Western Seoul Center, Korea Basic Science Institute, Seoul 03760, South Korea. Electronic address: sskang@ewha.ac.kr.</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea; Western Seoul Center, Korea Basic Science Institute, Seoul 03760</wicri:regionArea><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author></analytic><series><title level="j">Bioorganic & medicinal chemistry letters</title><idno type="eISSN">1464-3405</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">As the most abundant heat shock protein (HSP), Hsp90 is actively involved in tumor cell growth and various responses to anti-carcinogenic stress. Hsp90 has thus emerged as a potential drug target. A structure-based drug design approach was applied to develop novel resorcinolyltriazole derivatives as Hsp90 inhibitors. Structure-activity relationships (SARs) and molecular docking were investigated to provide a rationale for binding affinity and paralog selectivity. Click chemistry between iodoethynylresorcinol and an azido derivative was used to synthesize a new family of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl) acetates that exhibited Hsp90 binding affinities of 40-100 nM (IC<sub>50</sub>). Among the synthesized molecules, the triazole alkyl acetates displayed the highest Hsp90 binding affinities. Their potency against Hsp90 was over 100-fold stronger than against TRAP1 and 1-3-fold stronger than against Grp94. In particular, compounds 18, 19, and 30 had Hsp90 inhibitory activities of ~45 nM (IC<sub>50</sub>) and they displayed over 350-fold selectivity for Hsp90 over TRAP1.</div></front></TEI><affiliations><list><country><li>Corée du Sud</li></country><region><li>Région capitale de Séoul</li></region><settlement><li>Séoul</li></settlement></list><tree><country name="Corée du Sud"><noRegion><name sortKey="Jung, Sejin" sort="Jung, Sejin" uniqKey="Jung S" first="Sejin" last="Jung">Sejin Jung</name></noRegion><name sortKey="Hong, Ki Bum" sort="Hong, Ki Bum" uniqKey="Hong K" first="Ki Bum" last="Hong">Ki Bum Hong</name><name sortKey="Kang, Byoung Heon" sort="Kang, Byoung Heon" uniqKey="Kang B" first="Byoung Heon" last="Kang">Byoung Heon Kang</name><name sortKey="Kang, Soosung" sort="Kang, Soosung" uniqKey="Kang S" first="Soosung" last="Kang">Soosung Kang</name><name sortKey="Kim, Darong" sort="Kim, Darong" uniqKey="Kim D" first="Darong" last="Kim">Darong Kim</name><name sortKey="Lee, Changwook" sort="Lee, Changwook" uniqKey="Lee C" first="Changwook" last="Lee">Changwook Lee</name><name sortKey="Lee, Ji Hoon" sort="Lee, Ji Hoon" uniqKey="Lee J" first="Ji Hoon" last="Lee">Ji Hoon Lee</name><name sortKey="Lee, Won Seok" sort="Lee, Won Seok" uniqKey="Lee W" first="Won Seok" last="Lee">Won Seok Lee</name><name sortKey="Yang, Sujae" sort="Yang, Sujae" uniqKey="Yang S" first="Sujae" last="Yang">Sujae Yang</name><name sortKey="Yoon, Nam Gu" sort="Yoon, Nam Gu" uniqKey="Yoon N" first="Nam Gu" last="Yoon">Nam Gu Yoon</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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