Blocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small molecule
Abstract X-linked inhibitor of apoptosis (XIAP) inhibits caspases 3, 7, and 9, thereby preventing cell apoptosis. Endogenous Second mitochondria-derived activator of caspase (Smac) competes out the binding of caspases with XIAP and causes apoptosis, so that Smac mimetics are under clinical trials fo...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07774-y |
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| author | Shih-Hsun Chen Szu-Ying Wu Yun-Xun Chang En-Ning Lui Chih-Kang Chang Sheng-Wei Lin Michael Hsiao Jinn-Moon Yang Po-Huang Liang |
| author_facet | Shih-Hsun Chen Szu-Ying Wu Yun-Xun Chang En-Ning Lui Chih-Kang Chang Sheng-Wei Lin Michael Hsiao Jinn-Moon Yang Po-Huang Liang |
| author_sort | Shih-Hsun Chen |
| collection | DOAJ |
| description | Abstract X-linked inhibitor of apoptosis (XIAP) inhibits caspases 3, 7, and 9, thereby preventing cell apoptosis. Endogenous Second mitochondria-derived activator of caspase (Smac) competes out the binding of caspases with XIAP and causes apoptosis, so that Smac mimetics are under clinical trials for anti-cancer chemotherapy. We demonstrated by selectively alkylating caspase 7 (CASP7) to release the active CASP7 for killing the drug-resistant cancer cells with accumulated XIAP:CASP7 resulted from caspase-3 down-regulation (CASP3/DR). However, finding a reversible inhibitor of the protein-protein interaction (PPI) poses a significant challenge. Here, we identified a reversible XIAP:CASP7 inhibitor, 643943, through a multiple-mode virtual screening strategy. In vitro experiments revealed that 643943 bound to CASP7, released the linker-BIR2 domain of XIAP, and activated the caspase. Removing an essential hydroxyl group on 643943 or replacing the OH-interacting Asp93 on CASP7 caused loss of 643943 cytotoxicity, revealing the binding mode. This compound thus selectively killed MCF-7 and other CASP3/DR triple-negative breast cancer cell lines, but not the cancer and normal cell lines expressing higher levels of CASP3 in vitro and in vivo. Moreover, 643943 overcame chemoresistance via down-regulating β-catenin and its associated ABC transporters in paclitaxel-resistant MCF-7 cells. Our studies not only serve as a proof-of-concept for using XIAP:CASP7 as a drug target, but also provide the first reversible XIAP:CASP7 inhibitor for cancer therapy of CASP3/DR malignancies. |
| format | Article |
| id | doaj-art-965d455fb220466db5354ffc956f0ff5 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-965d455fb220466db5354ffc956f0ff52025-08-20T03:22:57ZengNature Publishing GroupCell Death and Disease2041-48892025-06-0116111310.1038/s41419-025-07774-yBlocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small moleculeShih-Hsun Chen0Szu-Ying Wu1Yun-Xun Chang2En-Ning Lui3Chih-Kang Chang4Sheng-Wei Lin5Michael Hsiao6Jinn-Moon Yang7Po-Huang Liang8Institute of Biochemical Sciences, National Taiwan UniversityInstitute of Biochemical Sciences, National Taiwan UniversityInstitute of Biochemical Sciences, National Taiwan UniversityInstitute of Biochemical Sciences, National Taiwan UniversityInstitute of Biological Chemistry, Academia SinicaInstitute of Biological Chemistry, Academia SinicaGenomics Research Center, Academia SinicaDepartment of Biological Science and Technology, National Yang Ming Chiao Tung UniversityInstitute of Biochemical Sciences, National Taiwan UniversityAbstract X-linked inhibitor of apoptosis (XIAP) inhibits caspases 3, 7, and 9, thereby preventing cell apoptosis. Endogenous Second mitochondria-derived activator of caspase (Smac) competes out the binding of caspases with XIAP and causes apoptosis, so that Smac mimetics are under clinical trials for anti-cancer chemotherapy. We demonstrated by selectively alkylating caspase 7 (CASP7) to release the active CASP7 for killing the drug-resistant cancer cells with accumulated XIAP:CASP7 resulted from caspase-3 down-regulation (CASP3/DR). However, finding a reversible inhibitor of the protein-protein interaction (PPI) poses a significant challenge. Here, we identified a reversible XIAP:CASP7 inhibitor, 643943, through a multiple-mode virtual screening strategy. In vitro experiments revealed that 643943 bound to CASP7, released the linker-BIR2 domain of XIAP, and activated the caspase. Removing an essential hydroxyl group on 643943 or replacing the OH-interacting Asp93 on CASP7 caused loss of 643943 cytotoxicity, revealing the binding mode. This compound thus selectively killed MCF-7 and other CASP3/DR triple-negative breast cancer cell lines, but not the cancer and normal cell lines expressing higher levels of CASP3 in vitro and in vivo. Moreover, 643943 overcame chemoresistance via down-regulating β-catenin and its associated ABC transporters in paclitaxel-resistant MCF-7 cells. Our studies not only serve as a proof-of-concept for using XIAP:CASP7 as a drug target, but also provide the first reversible XIAP:CASP7 inhibitor for cancer therapy of CASP3/DR malignancies.https://doi.org/10.1038/s41419-025-07774-y |
| spellingShingle | Shih-Hsun Chen Szu-Ying Wu Yun-Xun Chang En-Ning Lui Chih-Kang Chang Sheng-Wei Lin Michael Hsiao Jinn-Moon Yang Po-Huang Liang Blocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small molecule Cell Death and Disease |
| title | Blocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small molecule |
| title_full | Blocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small molecule |
| title_fullStr | Blocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small molecule |
| title_full_unstemmed | Blocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small molecule |
| title_short | Blocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small molecule |
| title_sort | blocking xiap casp7 p19 selectively induces apoptosis of casp3 dr malignancies by a novel reversible small molecule |
| url | https://doi.org/10.1038/s41419-025-07774-y |
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