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38 results on '"Stuckey, Jeanne A."'

1. Human SIRT5 variants with reduced stability and activity do not cause neuropathology in mice

Author

Yuan, Taolin, Kumar, Surinder, Skinner, Mary E., Victor-Joseph, Ryan, Abuaita, Majd, Keijer, Jaap, Zhang, Jessica, Kunkel, Thaddeus J., Liu, Yanghan, Petrunak, Elyse M., Saunders, Thomas L., Lieberman, Andrew P., Stuckey, Jeanne A., Neamati, Nouri, Al-Murshedi, Fathiya, Alfadhel, Majid, Spelbrink, Johannes N., Rodenburg, Richard, de Boer, Vincent C.J., and Lombard, David B.

Published
2024
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5. SIRT5 variants from patients with mitochondrial disease are associated with reduced SIRT5 stability and activity, but not with neuropathology

Author

Yuan, Taolin, primary, Kumar, Surinder, additional, Skinner, Mary E, additional, Victor-Joseph, Ryan, additional, Abuaita, Majd, additional, Keijer, Jaap, additional, Zhang, Jessica, additional, Kunkel, Thaddeus, additional, Liu, Yanghan, additional, Petrunak, Elyse, additional, Saunders, Thomas, additional, Lieberman, Andrew P., additional, Stuckey, Jeanne A., additional, Neamati, Nouri, additional, AlMurshedi, Fathiya, additional, Alfadhel, Majid, additional, Spelbrink, Johannes N, additional, Rodenburg, Richard, additional, de Boer, Vincent C.J., additional, and Lombard, David B, additional

Published
2023
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6. Prophylactic Mitigation of Acute Graft versus Host Disease by Novel 2-(Pyrrolidin-1-ylmethyl)pyrrole-Based Stimulation-2 (ST2) Inhibitors

Author

Yuan, Xinrui, primary, Jiang, Hua, additional, Fu, Denggang, additional, Rech, Jason C., additional, Robida, Aaron, additional, Rajanayake, Krishani, additional, Yuan, Hebao, additional, He, Miao, additional, Wen, Bo, additional, Sun, Duxin, additional, Liu, Chen, additional, Chinnaswamy, Krishnapriya, additional, Stuckey, Jeanne A., additional, Paczesny, Sophie, additional, and Yang, Chao-Yie, additional

Published
2023
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10. Data from A Novel Small-Molecule Inhibitor of Mcl-1 Blocks Pancreatic Cancer Growth In Vitro and In Vivo

Author

Abulwerdi, Fardokht, primary, Liao, Chenzhong, primary, Liu, Meilan, primary, Azmi, Asfar S., primary, Aboukameel, Amro, primary, Mady, Ahmed S.A., primary, Gulappa, Thippeswamy, primary, Cierpicki, Tomasz, primary, Owens, Scott, primary, Zhang, Tao, primary, Sun, Duxin, primary, Stuckey, Jeanne A., primary, Mohammad, Ramzi M., primary, and Nikolovska-Coleska, Zaneta, primary

Published
2023
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11. Supplementary Methods and Supplementary Figures 1 through 9 from A Novel Small-Molecule Inhibitor of Mcl-1 Blocks Pancreatic Cancer Growth In Vitro and In Vivo

Author

Abulwerdi, Fardokht, primary, Liao, Chenzhong, primary, Liu, Meilan, primary, Azmi, Asfar S., primary, Aboukameel, Amro, primary, Mady, Ahmed S.A., primary, Gulappa, Thippeswamy, primary, Cierpicki, Tomasz, primary, Owens, Scott, primary, Zhang, Tao, primary, Sun, Duxin, primary, Stuckey, Jeanne A., primary, Mohammad, Ramzi M., primary, and Nikolovska-Coleska, Zaneta, primary

Published
2023
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12. Supplementary Figures from Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy

Author

Deng, Jing, primary, Paulus, Aneel, primary, Fang, Douglas D., primary, Manna, Alak, primary, Wang, Guangfeng, primary, Wang, Hengbang, primary, Zhu, Saijie, primary, Chen, Jianyong, primary, Min, Ping, primary, Yin, Yan, primary, Dutta, Navnita, primary, Halder, Nabanita, primary, Ciccio, Gina, primary, Copland, John A., primary, Miller, James, primary, Han, Bing, primary, Bai, Longchuan, primary, Liu, Liu, primary, Wang, Mi, primary, McEachern, Donna, primary, Przybranowski, Sally, primary, Yang, Chao-Yie, primary, Stuckey, Jeanne A., primary, Wu, Depei, primary, Li, Caixia, primary, Ryan, Jeremy, primary, Letai, Anthony, primary, Ailawadhi, Sikander, primary, Yang, Dajun, primary, Wang, Shaomeng, primary, Chanan-Khan, Asher, primary, and Zhai, Yifan, primary

Published
2023
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13. Supplementary Tables from Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy

Author

Deng, Jing, primary, Paulus, Aneel, primary, Fang, Douglas D., primary, Manna, Alak, primary, Wang, Guangfeng, primary, Wang, Hengbang, primary, Zhu, Saijie, primary, Chen, Jianyong, primary, Min, Ping, primary, Yin, Yan, primary, Dutta, Navnita, primary, Halder, Nabanita, primary, Ciccio, Gina, primary, Copland, John A., primary, Miller, James, primary, Han, Bing, primary, Bai, Longchuan, primary, Liu, Liu, primary, Wang, Mi, primary, McEachern, Donna, primary, Przybranowski, Sally, primary, Yang, Chao-Yie, primary, Stuckey, Jeanne A., primary, Wu, Depei, primary, Li, Caixia, primary, Ryan, Jeremy, primary, Letai, Anthony, primary, Ailawadhi, Sikander, primary, Yang, Dajun, primary, Wang, Shaomeng, primary, Chanan-Khan, Asher, primary, and Zhai, Yifan, primary

Published
2023
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14. Supplementary Data from Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy

Author

Deng, Jing, primary, Paulus, Aneel, primary, Fang, Douglas D., primary, Manna, Alak, primary, Wang, Guangfeng, primary, Wang, Hengbang, primary, Zhu, Saijie, primary, Chen, Jianyong, primary, Min, Ping, primary, Yin, Yan, primary, Dutta, Navnita, primary, Halder, Nabanita, primary, Ciccio, Gina, primary, Copland, John A., primary, Miller, James, primary, Han, Bing, primary, Bai, Longchuan, primary, Liu, Liu, primary, Wang, Mi, primary, McEachern, Donna, primary, Przybranowski, Sally, primary, Yang, Chao-Yie, primary, Stuckey, Jeanne A., primary, Wu, Depei, primary, Li, Caixia, primary, Ryan, Jeremy, primary, Letai, Anthony, primary, Ailawadhi, Sikander, primary, Yang, Dajun, primary, Wang, Shaomeng, primary, Chanan-Khan, Asher, primary, and Zhai, Yifan, primary

Published
2023
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15. Supporting Information: Tables from Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer

Author

Bai, Longchuan, primary, Zhou, Bing, primary, Yang, Chao-Yie, primary, Ji, Jiao, primary, McEachern, Donna, primary, Przybranowski, Sally, primary, Jiang, Hui, primary, Hu, Jiantao, primary, Xu, Fuming, primary, Zhao, Yujun, primary, Liu, Liu, primary, Fernandez-Salas, Ester, primary, Xu, Jing, primary, Dou, Yali, primary, Wen, Bo, primary, Sun, Duxin, primary, Meagher, Jennifer, primary, Stuckey, Jeanne, primary, Hayes, Daniel F., primary, Li, Shunqiang, primary, Ellis, Matthew J., primary, and Wang, Shaomeng, primary

Published
2023
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16. Supporting Information: Figures from Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer

Author

Bai, Longchuan, primary, Zhou, Bing, primary, Yang, Chao-Yie, primary, Ji, Jiao, primary, McEachern, Donna, primary, Przybranowski, Sally, primary, Jiang, Hui, primary, Hu, Jiantao, primary, Xu, Fuming, primary, Zhao, Yujun, primary, Liu, Liu, primary, Fernandez-Salas, Ester, primary, Xu, Jing, primary, Dou, Yali, primary, Wen, Bo, primary, Sun, Duxin, primary, Meagher, Jennifer, primary, Stuckey, Jeanne, primary, Hayes, Daniel F., primary, Li, Shunqiang, primary, Ellis, Matthew J., primary, and Wang, Shaomeng, primary

Published
2023
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17. Supporting Information: Methods from Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer

Author

Bai, Longchuan, primary, Zhou, Bing, primary, Yang, Chao-Yie, primary, Ji, Jiao, primary, McEachern, Donna, primary, Przybranowski, Sally, primary, Jiang, Hui, primary, Hu, Jiantao, primary, Xu, Fuming, primary, Zhao, Yujun, primary, Liu, Liu, primary, Fernandez-Salas, Ester, primary, Xu, Jing, primary, Dou, Yali, primary, Wen, Bo, primary, Sun, Duxin, primary, Meagher, Jennifer, primary, Stuckey, Jeanne, primary, Hayes, Daniel F., primary, Li, Shunqiang, primary, Ellis, Matthew J., primary, and Wang, Shaomeng, primary

Published
2023
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18. Data from Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer

Author

Bai, Longchuan, primary, Zhou, Bing, primary, Yang, Chao-Yie, primary, Ji, Jiao, primary, McEachern, Donna, primary, Przybranowski, Sally, primary, Jiang, Hui, primary, Hu, Jiantao, primary, Xu, Fuming, primary, Zhao, Yujun, primary, Liu, Liu, primary, Fernandez-Salas, Ester, primary, Xu, Jing, primary, Dou, Yali, primary, Wen, Bo, primary, Sun, Duxin, primary, Meagher, Jennifer, primary, Stuckey, Jeanne, primary, Hayes, Daniel F., primary, Li, Shunqiang, primary, Ellis, Matthew J., primary, and Wang, Shaomeng, primary

Published
2023
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19. Data from SM-164: A Novel, Bivalent Smac Mimetic That Induces Apoptosis and Tumor Regression by Concurrent Removal of the Blockade of cIAP-1/2 and XIAP

Author

Lu, Jianfeng, primary, Bai, Longchuan, primary, Sun, Haiying, primary, Nikolovska-Coleska, Zaneta, primary, McEachern, Donna, primary, Qiu, Su, primary, Miller, Rebecca S., primary, Yi, Han, primary, Shangary, Sanjeev, primary, Sun, Yi, primary, Meagher, Jennifer L., primary, Stuckey, Jeanne A., primary, and Wang, Shaomeng, primary

Published
2023
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20. Supplementary Methods, Figures 1-15 from SM-164: A Novel, Bivalent Smac Mimetic That Induces Apoptosis and Tumor Regression by Concurrent Removal of the Blockade of cIAP-1/2 and XIAP

Author

Lu, Jianfeng, primary, Bai, Longchuan, primary, Sun, Haiying, primary, Nikolovska-Coleska, Zaneta, primary, McEachern, Donna, primary, Qiu, Su, primary, Miller, Rebecca S., primary, Yi, Han, primary, Shangary, Sanjeev, primary, Sun, Yi, primary, Meagher, Jennifer L., primary, Stuckey, Jeanne A., primary, and Wang, Shaomeng, primary

Published
2023
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21. Three Supplementary Tables and Supplementary Figures S1-S13 from SAR405838: An Optimized Inhibitor of MDM2–p53 Interaction That Induces Complete and Durable Tumor Regression

Author

Wang, Shaomeng, primary, Sun, Wei, primary, Zhao, Yujun, primary, McEachern, Donna, primary, Meaux, Isabelle, primary, Barrière, Cédric, primary, Stuckey, Jeanne A., primary, Meagher, Jennifer L., primary, Bai, Longchuan, primary, Liu, Liu, primary, Hoffman-Luca, Cassandra Gianna, primary, Lu, Jianfeng, primary, Shangary, Sanjeev, primary, Yu, Shanghai, primary, Bernard, Denzil, primary, Aguilar, Angelo, primary, Dos-Santos, Odette, primary, Besret, Laurent, primary, Guerif, Stéphane, primary, Pannier, Pascal, primary, Gorge-Bernat, Dimitri, primary, and Debussche, Laurent, primary

Published
2023
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22. Data from SAR405838: An Optimized Inhibitor of MDM2–p53 Interaction That Induces Complete and Durable Tumor Regression

Author

Wang, Shaomeng, primary, Sun, Wei, primary, Zhao, Yujun, primary, McEachern, Donna, primary, Meaux, Isabelle, primary, Barrière, Cédric, primary, Stuckey, Jeanne A., primary, Meagher, Jennifer L., primary, Bai, Longchuan, primary, Liu, Liu, primary, Hoffman-Luca, Cassandra Gianna, primary, Lu, Jianfeng, primary, Shangary, Sanjeev, primary, Yu, Shanghai, primary, Bernard, Denzil, primary, Aguilar, Angelo, primary, Dos-Santos, Odette, primary, Besret, Laurent, primary, Guerif, Stéphane, primary, Pannier, Pascal, primary, Gorge-Bernat, Dimitri, primary, and Debussche, Laurent, primary

Published
2023
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25. Novel Chemical Series of Anti-ST2 Small Molecules Suppress Allogeneic T Cells Proliferation While Increasing Treg Cells and Improve Gvhd and Survival In Vivo

Author

Yang, Chao-Yie, primary, Yuan, Xinrui, additional, Jiang, Hua, additional, Rech, Jason C., additional, Fu, Denggang, additional, Robida, Aaron, additional, Rajanayake, Krishani, additional, Yuan, Hebao, additional, Wen, Bo, additional, Sun, Duxin, additional, Chinnaswamy, Krishnapriya, additional, Stuckey, Jeanne A., additional, and Paczesny, Sophie, additional

Published
2022
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26. Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy

Author

Deng, Jing, primary, Paulus, Aneel, additional, Fang, Douglas D., additional, Manna, Alak, additional, Wang, Guangfeng, additional, Wang, Hengbang, additional, Zhu, Saijie, additional, Chen, Jianyong, additional, Min, Ping, additional, Yin, Yan, additional, Dutta, Navnita, additional, Halder, Nabanita, additional, Ciccio, Gina, additional, Copland, John A., additional, Miller, James, additional, Han, Bing, additional, Bai, Longchuan, additional, Liu, Liu, additional, Wang, Mi, additional, McEachern, Donna, additional, Przybranowski, Sally, additional, Yang, Chao-Yie, additional, Stuckey, Jeanne A., additional, Wu, Depei, additional, Li, Caixia, additional, Ryan, Jeremy, additional, Letai, Anthony, additional, Ailawadhi, Sikander, additional, Yang, Dajun, additional, Wang, Shaomeng, additional, Chanan-Khan, Asher, additional, and Zhai, Yifan, additional

Published
2022
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29. Structure-Activity Relationship of 1-(Furan-2ymethyl)Pyrrolidinebbased Stimulation-2 (ST2) Inhibitors for Treating Graft Versus Host Disease

Author

Yuan, Xinrui, primary, Jiang, Hua, additional, Fu, Denggang, additional, Robida, Aaron, additional, Rajanayake, Krishani, additional, Yuan, Hebao, additional, Wen, Bo, additional, Sun, Duxin, additional, Watch, Brennan T., additional, Chinnaswamy, Krishnapriya, additional, Stuckey, Jeanne A., additional, Paczesny, Sophie, additional, Rech, Jason C., additional, and Yang, Chao-Yie, additional

Published
2022
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31. Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivoin Acute Myeloid Leukemia

Author

Kaneshige, Atsunori, Bai, Longchuan, Wang, Mi, McEachern, Donna, Meagher, Jennifer L., Xu, Renqi, Kirchhoff, Paul D., Wen, Bo, Sun, Duxin, Stuckey, Jeanne A., and Wang, Shaomeng

Abstract

STAT5 is an attractive therapeutic target for human cancers. We report herein the discovery of a potent and selective STAT5 degrader with strong antitumor activity in vivo. We first obtained small-molecule ligands with sub-micromolar to low micromolar binding affinities to STAT5 and STAT6 SH2 domains and determined co-crystal structures of three such ligands in complex with STAT5A. We successfully transformed these ligands into potent and selective STAT5 degraders using the PROTAC technology with AK-2292 as the best compound. AK-2292 effectively induces degradation of STAT5A, STAT5B, and phosphorylated STAT5 proteins in a concentration- and time-dependent manner in acute myeloid leukemia (AML) cell lines and demonstrates excellent degradation selectivity for STAT5 over all other STAT members. It exerts potent and specific cell growth inhibitory activity in AML cell lines with high levels of phosphorylated STAT5. AK-2292 effectively reduces STAT5 protein in vivoand achieves strong antitumor activity in mice at well-tolerated dose schedules.

Published
2023
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33. Discovery of AK-1690: A Potent and Highly Selective STAT6 PROTAC Degrader

Author

Kaneshige, Atsunori, Yang, Yiqing, Bai, Longchuan, Wang, Mi, Xu, Renqi, Mallik, Leena, Chinnaswamy, Krishnapriya, Metwally, Hoda, Wang, Yu, McEachern, Donna, Tošović, Jelena, Yang, Chao-Yie, Kirchhoff, Paul D., Meagher, Jennifer L., Stuckey, Jeanne A., and Wang, Shaomeng

Abstract

STAT6 is an attractive therapeutic target for human cancers and other human diseases. Starting from a STAT6 ligand with Ki= 3.5 μM binding affinity, we obtained AK-068 with Ki= 6 nM to STAT6 and at least >85-fold binding selectivity over STAT5. Using AK-068 and cereblon ligands, we discovered AK-1690 as the first, potent and selective PROTAC STAT6 degrader. AK-1690 effectively induces degradation of STAT6 protein in cells with DC50values of as low as 1 nM while showing minimal effect on other STAT members up to 10 μM. A single dose of AK-1690 effectively depletes STAT6 in mouse tissues. Determination of the first cocrystal structure of STAT6 in complex with AK-1690 provides a structural basis for their interactions. AK-1690 is a powerful tool with which to investigate the roles of STAT6 in human diseases and biological processes and a promising lead compound for further optimization.

Published
2024
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34. High-Affinity Peptidomimetic Inhibitors of the DCN1-UBC12 Protein–Protein Interaction

Author

Zhou, Haibin, Zhou, Weihua, Zhou, Bing, Liu, Liu, Chern, Ting-Rong, Chinnaswamy, Krishnapriya, Lu, Jianfeng, Bernard, Denzil, Yang, Chao-Yie, Li, Shasha, Wang, Mi, Stuckey, Jeanne, Sun, Yi, and Wang, Shaomeng

Abstract

The Cullin-RING ligases (CRLs) regulate the turnover of approximately 20% of the proteins in mammalian cells and are emerging therapeutic targets in human diseases. The activation of CRLs requires the neddylation of their cullin subunit, which is controlled by an activation complex consisting of Cullin-RBX1-UBC12-NEDD8-DCN1. Herein, we describe the design, synthesis, and evaluation of peptidomimetics targeting the DCN1-UBC12 protein–protein interaction. Starting from a 12-residue UBC12 peptide, we have successfully obtained a series of peptidomimetic compounds that bind to DCN1 protein with KDvalues of <10 nM. Determination of a cocrystal structure of a potent peptidomimetic inhibitor complexed with DCN1 provides the structural basis for their high-affinity interaction. Cellular investigation of one potent DCN1 inhibitor, compound 36(DI-404), reveals that it effectively and selectively inhibits the neddylation of cullin 3 over other cullin members. Further optimization of DI-404 may yield a new class of therapeutics for the treatment of human diseases in which cullin 3 CRL plays a key role.

Published
2024
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35. Precise Conformational Control Yielding Highly Potent and Exceptionally Selective BRD4 Degraders with Strong Antitumor Activity

Author

Hu, Jiantao, Hu, Biao, Xu, Fuming, Wang, Mi, Qin, Chong, McEachern, Donna, Stuckey, Jeanne, and Wang, Shaomeng

Abstract

Starting from a nonselective bromodomain and extraterminal (BET) inhibitor and a cereblon ligand, we have used precise conformational control for the development of two potent and highly selective BRD4 degraders, BD-7148 and BD-9136. These compounds induce rapid degradation of BRD4 protein in cells at concentrations as low as 1 nM and demonstrate ≥1000-fold degradation selectivity over BRD2 or BRD3 protein. Proteomic analysis of >5700 proteins confirmed their highly selective BRD4 degradation. A single dose of BD-9136 selectively and effectively depletes BRD4 protein in tumor tissues for >48 h. BD-9136 effectively inhibits tumor growth without adverse effects on mice and is more efficacious than the corresponding pan BET inhibitor. This study suggests selective degradation of BRD4 as a strategy for the treatment of human cancers and demonstrates a strategy for the design of highly selective PROTAC degraders.

Published
2024
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36. Small-Molecule U2 Auxiliary Factor Homology Motif (UHM) Domain Inhibitors Cause Splicing Pattern Changes in U2AF1Mutant Leukemia Cells and Induce Sub-G1 Cell Cycle Arrest

Author

Yang, Chao-Yie, Yuan, Xinrui, Kazemi Sabzvar, Mona, Durmaz, Arda, Chinnaswamy, Krishnapriya, Stuckey, Jeanne, Corey, Seth J, Maciejewski, Jaroslaw P., and Visconte, Valeria

Abstract

Mutations in factors involved in the spliceosomal pathway have emerged to be an important contributor to the development of myeloid neoplasms including MDS and secondary AML (sAML). A set of frequently mutated genes encoding RNA splicing factors including SF3B1, U2AF1, SRSF2, and ZRSR2or haploinsufficiency of LUC7L2have beenreported, but pharmacological intervention targeting these genes remains limited and under-developed. Combination of mutations of these splicing factors are rarely found in patients indicating that multiple defects in a spliceosome pathway may be deleterious. Heterozygous mutation in U2AF1found in MDS leads to the acquisition of the neomorphic mutant U2AF1 (U2AF1 wt) that relies on wild-type U2AF1 (U2AF1 wt) to survive and proliferate.

Published
2023
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37. Comprehensive Analyses of the Effects of the Small-Molecule Inhibitor of the UHM Domain in the Splicing Factor U2AF1 in Leukemia Cells.

Author

Yuan X, Sabzvar MK, Patil AD, Chinnaswamy K, Howie KL, Andhavaram R, Wang B, Siegler MA, Dumaz A, Stuckey JA, Corey SJ, Maciejewski JP, Visconte V, and Yang CY

Abstract

Mutations in RNA splicing factor genes including SF3B1, U2AF1 , SRSF2 , and ZRSR2 have been reported to contribute to development of myeloid neoplasms including myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML). Chemical tools targeting cells carrying these mutant genes remain limited and underdeveloped. Among the four proteins, mutant U2AF1 (U2AF1 mut ) acquires an altered 3' splice site selection preference and co-operates with the wild-type U2AF1 (U2AF1 wt ) to change various gene isoform patterns to support MDS cells survival and proliferation. U2AF1 mutations in MDS cells are always heterozygous and the cell viability is reduced when exposed to additional insult affecting U2AF1 wt function. To investigate if the pharmacological inhibition of U2AF1 wt function can provoke drug-induced vulnerability of cells harboring U2AF1 , we conducted a fragment-based library screening campaign to discover compounds targeting the U2AF homology domain (UHM) in U2AF1 that is required for the formation of the U2AF1/U2AF2 complex to define the 3' splice site. The most promising hit ( mut , we conducted a fragment-based library screening campaign to discover compounds targeting the U2AF homology domain (UHM) in U2AF1 that is required for the formation of the U2AF1/U2AF2 complex to define the 3' splice site. The most promising hit ( SF1-8 ) selectively inhibited growth of leukemia cell lines overexpressing U2AF1 mut and human primary MDS cells carrying U2AF1 further revealed alteration of isoform patterns for a set of proteins that impair or rescue pathways associated with endocytosis, intracellular vesicle transport, and secretion. Our data suggested that further optimization of mut . RNA-seq analysis of K562-U2AF1 mut following treatment with SF1-8 further revealed alteration of isoform patterns for a set of proteins that impair or rescue pathways associated with endocytosis, intracellular vesicle transport, and secretion. Our data suggested that further optimization of SF1-8 is warranted to obtain chemical probes that can be used to evaluate the therapeutic concept of inducing lethality to U2AF1 mut cells by inhibiting the U2AF1 wt protein., Competing Interests: The authors declare no competing financial interests. Readers welcome to comment on the online version of the paper. Additional Declarations: There is NO Competing Interest.

Published
2024
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38. SIRT5 variants from patients with mitochondrial disease are associated with reduced SIRT5 stability and activity, but not with neuropathology.

Author

Yuan T, Kumar S, Skinner M, Victor-Joseph R, Abuaita M, Keijer J, Zhang J, Kunkel TJ, Liu Y, Petrunak EM, Saunders TL, Lieberman AP, Stuckey JA, Neamati N, Al-Murshedi F, Alfadhel M, Spelbrink JN, Rodenburg R, de Boer VCJ, and Lombard DB

Abstract

SIRT5 is a sirtuin deacylase that represents the major activity responsible for removal of negatively-charged lysine modifications, in the mitochondrial matrix and elsewhere in the cell. In benign cells and mouse models, under basal non-stressed conditions, the phenotypes of SIRT5 deficiency are generally quite subtle. Here, we identify two homozygous SIRT5 variants in human patients suffering from severe mitochondrial disease. Both variants, P114T and L128V, are associated with reduced SIRT5 protein stability and impaired biochemical activity, with no evidence of neomorphic or dominant negative properties. The crystal structure of the P114T enzyme was solved and shows only subtle deviations from wild-type. Via CRISPR-Cas9, we generate a mouse model that recapitulates the human P114T mutation; homozygotes show reduced SIRT5 levels and activity, but no obvious metabolic abnormalities, neuropathology or other gross evidence of severe disease. We conclude that these human SIRT5 variants most likely represent severe hypomorphs, and are likely not the primary pathogenic cause of the neuropathology observed in the patients., Competing Interests: Declaration of Interests: The authors declare no competing interests.

Published
2023
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