Discovery of a Novel Template, 7-Substituted 7-Deaza-4′-Thioadenosine Derivatives as Multi-Kinase Inhibitors
The development of anticancer drugs remains challenging owing to the potential for drug resistance. The simultaneous inhibition of multiple targets involved in cancer could overcome resistance, and these agents would exhibit higher potency than single-target inhibitors. Protein kinases represent a p...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/12/1290 |
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| author | Karishma K. Mashelkar Woong Sub Byun Hyejin Ko Kisu Sung Sushil K. Tripathi Seungchan An Yun A Yum Jee Youn Kwon Minjae Kim Gibae Kim Eun-Ji Kwon Hyuk Woo Lee Minsoo Noh Sang Kook Lee Lak Shin Jeong |
| author_facet | Karishma K. Mashelkar Woong Sub Byun Hyejin Ko Kisu Sung Sushil K. Tripathi Seungchan An Yun A Yum Jee Youn Kwon Minjae Kim Gibae Kim Eun-Ji Kwon Hyuk Woo Lee Minsoo Noh Sang Kook Lee Lak Shin Jeong |
| author_sort | Karishma K. Mashelkar |
| collection | DOAJ |
| description | The development of anticancer drugs remains challenging owing to the potential for drug resistance. The simultaneous inhibition of multiple targets involved in cancer could overcome resistance, and these agents would exhibit higher potency than single-target inhibitors. Protein kinases represent a promising target for the development of anticancer agents. As most multi-kinase inhibitors are heterocycles occupying only the hinge and hydrophobic region in the ATP binding site, we aimed to design multi-kinase inhibitors that would occupy the ribose pocket, along with the hinge and hydrophobic region, based on ATP-kinase interactions. Herein, we report the discovery of a novel 4′-thionucleoside template as a multi-kinase inhibitor with potent anticancer activity. The in vitro evaluation revealed a lead <b>1g</b> (7-acetylene-7-deaza-4′-thioadenosine) with potent anticancer activity, and marked inhibition of TRKA, CK1δ, and DYRK1A/1B kinases in the kinome scan assay. We believe that these findings will pave the way for developing anticancer drugs. |
| first_indexed | 2024-03-10T03:20:26Z |
| format | Article |
| id | doaj.art-6a327eedf4e041f083764e0fd7c848a5 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T03:20:26Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-6a327eedf4e041f083764e0fd7c848a52023-11-23T10:03:38ZengMDPI AGPharmaceuticals1424-82472021-12-011412129010.3390/ph14121290Discovery of a Novel Template, 7-Substituted 7-Deaza-4′-Thioadenosine Derivatives as Multi-Kinase InhibitorsKarishma K. Mashelkar0Woong Sub Byun1Hyejin Ko2Kisu Sung3Sushil K. Tripathi4Seungchan An5Yun A Yum6Jee Youn Kwon7Minjae Kim8Gibae Kim9Eun-Ji Kwon10Hyuk Woo Lee11Minsoo Noh12Sang Kook Lee13Lak Shin Jeong14Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaFuture Medicine Co., Ltd., Seongnam 13449, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, KoreaThe development of anticancer drugs remains challenging owing to the potential for drug resistance. The simultaneous inhibition of multiple targets involved in cancer could overcome resistance, and these agents would exhibit higher potency than single-target inhibitors. Protein kinases represent a promising target for the development of anticancer agents. As most multi-kinase inhibitors are heterocycles occupying only the hinge and hydrophobic region in the ATP binding site, we aimed to design multi-kinase inhibitors that would occupy the ribose pocket, along with the hinge and hydrophobic region, based on ATP-kinase interactions. Herein, we report the discovery of a novel 4′-thionucleoside template as a multi-kinase inhibitor with potent anticancer activity. The in vitro evaluation revealed a lead <b>1g</b> (7-acetylene-7-deaza-4′-thioadenosine) with potent anticancer activity, and marked inhibition of TRKA, CK1δ, and DYRK1A/1B kinases in the kinome scan assay. We believe that these findings will pave the way for developing anticancer drugs.https://www.mdpi.com/1424-8247/14/12/12907-deaza-4′-thioadenosine derivativesmulti-kinase inhibitoranticancernucleoside |
| spellingShingle | Karishma K. Mashelkar Woong Sub Byun Hyejin Ko Kisu Sung Sushil K. Tripathi Seungchan An Yun A Yum Jee Youn Kwon Minjae Kim Gibae Kim Eun-Ji Kwon Hyuk Woo Lee Minsoo Noh Sang Kook Lee Lak Shin Jeong Discovery of a Novel Template, 7-Substituted 7-Deaza-4′-Thioadenosine Derivatives as Multi-Kinase Inhibitors Pharmaceuticals 7-deaza-4′-thioadenosine derivatives multi-kinase inhibitor anticancer nucleoside |
| title | Discovery of a Novel Template, 7-Substituted 7-Deaza-4′-Thioadenosine Derivatives as Multi-Kinase Inhibitors |
| title_full | Discovery of a Novel Template, 7-Substituted 7-Deaza-4′-Thioadenosine Derivatives as Multi-Kinase Inhibitors |
| title_fullStr | Discovery of a Novel Template, 7-Substituted 7-Deaza-4′-Thioadenosine Derivatives as Multi-Kinase Inhibitors |
| title_full_unstemmed | Discovery of a Novel Template, 7-Substituted 7-Deaza-4′-Thioadenosine Derivatives as Multi-Kinase Inhibitors |
| title_short | Discovery of a Novel Template, 7-Substituted 7-Deaza-4′-Thioadenosine Derivatives as Multi-Kinase Inhibitors |
| title_sort | discovery of a novel template 7 substituted 7 deaza 4 thioadenosine derivatives as multi kinase inhibitors |
| topic | 7-deaza-4′-thioadenosine derivatives multi-kinase inhibitor anticancer nucleoside |
| url | https://www.mdpi.com/1424-8247/14/12/1290 |
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