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Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydrox...

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Autores principales: Wang, Zhiqiang, Zhang, Zhibo, Li, Yong, Sun, Li, Peng, Dezhen, Du, Danyu, Zhang, Xian, Han, Luwei, Zhao, Liwen, Lu, Ligong, Du, Hongzhi, Yuan, Shengtao, Zhan, Meixiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245910/
https://www.ncbi.nlm.nih.gov/pubmed/34221866
http://dx.doi.org/10.1016/j.apsb.2021.03.005
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author Wang, Zhiqiang
Zhang, Zhibo
Li, Yong
Sun, Li
Peng, Dezhen
Du, Danyu
Zhang, Xian
Han, Luwei
Zhao, Liwen
Lu, Ligong
Du, Hongzhi
Yuan, Shengtao
Zhan, Meixiao
author_facet Wang, Zhiqiang
Zhang, Zhibo
Li, Yong
Sun, Li
Peng, Dezhen
Du, Danyu
Zhang, Xian
Han, Luwei
Zhao, Liwen
Lu, Ligong
Du, Hongzhi
Yuan, Shengtao
Zhan, Meixiao
author_sort Wang, Zhiqiang
collection PubMed
description Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.
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spelling pubmed-82459102021-07-02 Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China Wang, Zhiqiang Zhang, Zhibo Li, Yong Sun, Li Peng, Dezhen Du, Danyu Zhang, Xian Han, Luwei Zhao, Liwen Lu, Ligong Du, Hongzhi Yuan, Shengtao Zhan, Meixiao Acta Pharm Sin B Original Article Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe. Elsevier 2021-06 2021-03-09 /pmc/articles/PMC8245910/ /pubmed/34221866 http://dx.doi.org/10.1016/j.apsb.2021.03.005 Text en © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Wang, Zhiqiang
Zhang, Zhibo
Li, Yong
Sun, Li
Peng, Dezhen
Du, Danyu
Zhang, Xian
Han, Luwei
Zhao, Liwen
Lu, Ligong
Du, Hongzhi
Yuan, Shengtao
Zhan, Meixiao
Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China
title Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China
title_full Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China
title_fullStr Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China
title_full_unstemmed Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China
title_short Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China
title_sort preclinical efficacy against acute myeloid leukaemia of sh1573, a novel mutant idh2 inhibitor approved for clinical trials in china
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245910/
https://www.ncbi.nlm.nih.gov/pubmed/34221866
http://dx.doi.org/10.1016/j.apsb.2021.03.005
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