Targeting p21-activated kinase 4 (PAK4) with pyrazolo[3,4-d]pyrimidine derivative SPA7012 attenuates hepatic ischaemia-reperfusion injury in mice
p21-Activated kinase 4 (PAK4), one of the serine/threonine kinases activated by Rho-family GTPases, has been widely studied as an oncogenic protein that is overexpressed in many types of cancers. In our recent study, PAK4 upregulation was observed in mice exhibiting hepatic ischaemia-reperfusion (I/...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2022-12-01
|
| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2106478 |
| _version_ | 1811343114017701888 |
|---|---|
| author | Yuancheng Mao Eun Lee Xiaohui Yang Eun Ju Bae Raok Jeon Byung-Hyun Park |
| author_facet | Yuancheng Mao Eun Lee Xiaohui Yang Eun Ju Bae Raok Jeon Byung-Hyun Park |
| author_sort | Yuancheng Mao |
| collection | DOAJ |
| description | p21-Activated kinase 4 (PAK4), one of the serine/threonine kinases activated by Rho-family GTPases, has been widely studied as an oncogenic protein that is overexpressed in many types of cancers. In our recent study, PAK4 upregulation was observed in mice exhibiting hepatic ischaemia-reperfusion (I/R) and in liver transplantation patients. Liver I/R injury was also attenuated in Pak4 KO mice. Herein, we report a novel series of pyrazolo[3,4-d]pyrimidine derivatives of type I ½ PAK4 inhibitors. The most potent compound SPA7012 was evaluated to determine the pharmacological potential of PAK4 inhibitor in I/R injury in mice. Mice with I/R injury showed typical patterns of liver damage, as demonstrated by increases in serum levels of aminotransferases and proinflammatory cytokines, hepatocellular necrosis and apoptosis, and inflammatory cell infiltration, relative to sham mice. Conversely, intraperitoneal administration of SPA7012 dramatically attenuated biochemical and histopathologic changes. Mechanistically, stabilisation of nuclear factor-erythroid 2-related factor 2 (Nrf2), a master regulator of anti-oxidative response, was observed following SPA7012 treatment. SPA7012 treatment in primary hepatocytes also attenuated hypoxia-reoxygenation-induced apoptotic cell death and inflammation. Together, these results provide experimental evidence supporting the use of PAK4 inhibitors for alleviation of I/R-induced liver damage. |
| first_indexed | 2024-04-13T19:22:52Z |
| format | Article |
| id | doaj.art-e01ef43aaaac4945836b4a864de87839 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-04-13T19:22:52Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-e01ef43aaaac4945836b4a864de878392022-12-22T02:33:28ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-013712133214610.1080/14756366.2022.2106478Targeting p21-activated kinase 4 (PAK4) with pyrazolo[3,4-d]pyrimidine derivative SPA7012 attenuates hepatic ischaemia-reperfusion injury in miceYuancheng Mao0Eun Lee1Xiaohui Yang2Eun Ju Bae3Raok Jeon4Byung-Hyun Park5Department of Biochemistry and Research Institute for Endocrine Sciences, Jeonbuk National University Medical School, Jeonju, Republic of KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of KoreaSchool of Pharmacy, Jeonbuk National University, Jeonju, Republic of KoreaSchool of Pharmacy, Jeonbuk National University, Jeonju, Republic of KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of KoreaDepartment of Biochemistry and Research Institute for Endocrine Sciences, Jeonbuk National University Medical School, Jeonju, Republic of Koreap21-Activated kinase 4 (PAK4), one of the serine/threonine kinases activated by Rho-family GTPases, has been widely studied as an oncogenic protein that is overexpressed in many types of cancers. In our recent study, PAK4 upregulation was observed in mice exhibiting hepatic ischaemia-reperfusion (I/R) and in liver transplantation patients. Liver I/R injury was also attenuated in Pak4 KO mice. Herein, we report a novel series of pyrazolo[3,4-d]pyrimidine derivatives of type I ½ PAK4 inhibitors. The most potent compound SPA7012 was evaluated to determine the pharmacological potential of PAK4 inhibitor in I/R injury in mice. Mice with I/R injury showed typical patterns of liver damage, as demonstrated by increases in serum levels of aminotransferases and proinflammatory cytokines, hepatocellular necrosis and apoptosis, and inflammatory cell infiltration, relative to sham mice. Conversely, intraperitoneal administration of SPA7012 dramatically attenuated biochemical and histopathologic changes. Mechanistically, stabilisation of nuclear factor-erythroid 2-related factor 2 (Nrf2), a master regulator of anti-oxidative response, was observed following SPA7012 treatment. SPA7012 treatment in primary hepatocytes also attenuated hypoxia-reoxygenation-induced apoptotic cell death and inflammation. Together, these results provide experimental evidence supporting the use of PAK4 inhibitors for alleviation of I/R-induced liver damage.https://www.tandfonline.com/doi/10.1080/14756366.2022.2106478PAK4pyrazolo[3,4-d]pyrimidineliverischaemia-reperfusionhypoxia-reoxygenationNrf2 |
| spellingShingle | Yuancheng Mao Eun Lee Xiaohui Yang Eun Ju Bae Raok Jeon Byung-Hyun Park Targeting p21-activated kinase 4 (PAK4) with pyrazolo[3,4-d]pyrimidine derivative SPA7012 attenuates hepatic ischaemia-reperfusion injury in mice Journal of Enzyme Inhibition and Medicinal Chemistry PAK4 pyrazolo[3,4-d]pyrimidine liver ischaemia-reperfusion hypoxia-reoxygenation Nrf2 |
| title | Targeting p21-activated kinase 4 (PAK4) with pyrazolo[3,4-d]pyrimidine derivative SPA7012 attenuates hepatic ischaemia-reperfusion injury in mice |
| title_full | Targeting p21-activated kinase 4 (PAK4) with pyrazolo[3,4-d]pyrimidine derivative SPA7012 attenuates hepatic ischaemia-reperfusion injury in mice |
| title_fullStr | Targeting p21-activated kinase 4 (PAK4) with pyrazolo[3,4-d]pyrimidine derivative SPA7012 attenuates hepatic ischaemia-reperfusion injury in mice |
| title_full_unstemmed | Targeting p21-activated kinase 4 (PAK4) with pyrazolo[3,4-d]pyrimidine derivative SPA7012 attenuates hepatic ischaemia-reperfusion injury in mice |
| title_short | Targeting p21-activated kinase 4 (PAK4) with pyrazolo[3,4-d]pyrimidine derivative SPA7012 attenuates hepatic ischaemia-reperfusion injury in mice |
| title_sort | targeting p21 activated kinase 4 pak4 with pyrazolo 3 4 d pyrimidine derivative spa7012 attenuates hepatic ischaemia reperfusion injury in mice |
| topic | PAK4 pyrazolo[3,4-d]pyrimidine liver ischaemia-reperfusion hypoxia-reoxygenation Nrf2 |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2106478 |
| work_keys_str_mv | AT yuanchengmao targetingp21activatedkinase4pak4withpyrazolo34dpyrimidinederivativespa7012attenuateshepaticischaemiareperfusioninjuryinmice AT eunlee targetingp21activatedkinase4pak4withpyrazolo34dpyrimidinederivativespa7012attenuateshepaticischaemiareperfusioninjuryinmice AT xiaohuiyang targetingp21activatedkinase4pak4withpyrazolo34dpyrimidinederivativespa7012attenuateshepaticischaemiareperfusioninjuryinmice AT eunjubae targetingp21activatedkinase4pak4withpyrazolo34dpyrimidinederivativespa7012attenuateshepaticischaemiareperfusioninjuryinmice AT raokjeon targetingp21activatedkinase4pak4withpyrazolo34dpyrimidinederivativespa7012attenuateshepaticischaemiareperfusioninjuryinmice AT byunghyunpark targetingp21activatedkinase4pak4withpyrazolo34dpyrimidinederivativespa7012attenuateshepaticischaemiareperfusioninjuryinmice |