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Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants
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| Zeitschriftentitel: | Cancer Science |
|---|---|
| Personen und Körperschaften: | , , , , , , , , |
| In: | Cancer Science, 110, 2019, 10, S. 3306-3314 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| author_facet |
Gao, Mingzhao Zhu, Hongmei Fu, Li Li, Yun Bao, Xubin Fu, Haoyu Quan, Haitian Wang, Lei Lou, Liguang Gao, Mingzhao Zhu, Hongmei Fu, Li Li, Yun Bao, Xubin Fu, Haoyu Quan, Haitian Wang, Lei Lou, Liguang |
|---|---|
| author |
Gao, Mingzhao Zhu, Hongmei Fu, Li Li, Yun Bao, Xubin Fu, Haoyu Quan, Haitian Wang, Lei Lou, Liguang |
| spellingShingle |
Gao, Mingzhao Zhu, Hongmei Fu, Li Li, Yun Bao, Xubin Fu, Haoyu Quan, Haitian Wang, Lei Lou, Liguang Cancer Science Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants Cancer Research Oncology General Medicine |
| author_sort |
gao, mingzhao |
| spelling |
Gao, Mingzhao Zhu, Hongmei Fu, Li Li, Yun Bao, Xubin Fu, Haoyu Quan, Haitian Wang, Lei Lou, Liguang 1347-9032 1349-7006 Wiley Cancer Research Oncology General Medicine http://dx.doi.org/10.1111/cas.14152 <jats:title>Abstract</jats:title><jats:p>Isocitrate dehydrogenase 2 (<jats:styled-content style="fixed-case">IDH</jats:styled-content>2), an important mitochondrial metabolic enzyme involved in the tricarboxylic acid cycle, is mutated in a variety of cancers. <jats:styled-content style="fixed-case">AG</jats:styled-content>‐221, an inhibitor primarily targeting the <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q mutant, has shown remarkable clinical benefits in the treatment of relapsed or refractory acute myeloid leukemia patients. However, <jats:styled-content style="fixed-case">AG</jats:styled-content>‐221 has weak inhibitory activity toward <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, a mutant form of <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 with more severe clinical manifestations. Herein, we report <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 as the first mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 inhibitor that potently targets both <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K mutants. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 inhibited mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 enzymatic activity, suppressed (R)‐2‐hydroxyglutarate (2‐<jats:styled-content style="fixed-case">HG</jats:styled-content>) production and induced differentiation in cells expressing <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, but not in cells expressing wild‐type <jats:styled-content style="fixed-case">IDH</jats:styled-content>1/2 or mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>1. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 bound to both <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, with Q316 being the critical residue mediating the binding of <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 with <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q, but not with <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 also had favorable pharmacokinetic characteristics and profoundly inhibited 2‐<jats:styled-content style="fixed-case">HG</jats:styled-content> production in a tumor xenografts model. The results of the current study establish a solid foundation for further clinical investigation of <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310, and provide new insight into the development of novel mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 inhibitors.</jats:p> Pharmacological characterization of <scp>TQ</scp>05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants Cancer Science |
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10.1111/cas.14152 |
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Wiley, 2019 |
| imprint_str_mv |
Wiley, 2019 |
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1347-9032 1349-7006 |
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1347-9032 1349-7006 |
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2019 |
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Cancer Science |
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49 |
| title |
Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| title_unstemmed |
Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| title_full |
Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| title_fullStr |
Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| title_full_unstemmed |
Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| title_short |
Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| title_sort |
pharmacological characterization of <scp>tq</scp>05310, a potent inhibitor of isocitrate dehydrogenase 2 r140q and r172k mutants |
| topic |
Cancer Research Oncology General Medicine |
| url |
http://dx.doi.org/10.1111/cas.14152 |
| publishDate |
2019 |
| physical |
3306-3314 |
| description |
<jats:title>Abstract</jats:title><jats:p>Isocitrate dehydrogenase 2 (<jats:styled-content style="fixed-case">IDH</jats:styled-content>2), an important mitochondrial metabolic enzyme involved in the tricarboxylic acid cycle, is mutated in a variety of cancers. <jats:styled-content style="fixed-case">AG</jats:styled-content>‐221, an inhibitor primarily targeting the <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q mutant, has shown remarkable clinical benefits in the treatment of relapsed or refractory acute myeloid leukemia patients. However, <jats:styled-content style="fixed-case">AG</jats:styled-content>‐221 has weak inhibitory activity toward <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, a mutant form of <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 with more severe clinical manifestations. Herein, we report <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 as the first mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 inhibitor that potently targets both <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K mutants. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 inhibited mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 enzymatic activity, suppressed (R)‐2‐hydroxyglutarate (2‐<jats:styled-content style="fixed-case">HG</jats:styled-content>) production and induced differentiation in cells expressing <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, but not in cells expressing wild‐type <jats:styled-content style="fixed-case">IDH</jats:styled-content>1/2 or mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>1. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 bound to both <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, with Q316 being the critical residue mediating the binding of <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 with <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q, but not with <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 also had favorable pharmacokinetic characteristics and profoundly inhibited 2‐<jats:styled-content style="fixed-case">HG</jats:styled-content> production in a tumor xenografts model. The results of the current study establish a solid foundation for further clinical investigation of <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310, and provide new insight into the development of novel mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 inhibitors.</jats:p> |
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| author | Gao, Mingzhao, Zhu, Hongmei, Fu, Li, Li, Yun, Bao, Xubin, Fu, Haoyu, Quan, Haitian, Wang, Lei, Lou, Liguang |
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| description | <jats:title>Abstract</jats:title><jats:p>Isocitrate dehydrogenase 2 (<jats:styled-content style="fixed-case">IDH</jats:styled-content>2), an important mitochondrial metabolic enzyme involved in the tricarboxylic acid cycle, is mutated in a variety of cancers. <jats:styled-content style="fixed-case">AG</jats:styled-content>‐221, an inhibitor primarily targeting the <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q mutant, has shown remarkable clinical benefits in the treatment of relapsed or refractory acute myeloid leukemia patients. However, <jats:styled-content style="fixed-case">AG</jats:styled-content>‐221 has weak inhibitory activity toward <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, a mutant form of <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 with more severe clinical manifestations. Herein, we report <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 as the first mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 inhibitor that potently targets both <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K mutants. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 inhibited mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 enzymatic activity, suppressed (R)‐2‐hydroxyglutarate (2‐<jats:styled-content style="fixed-case">HG</jats:styled-content>) production and induced differentiation in cells expressing <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, but not in cells expressing wild‐type <jats:styled-content style="fixed-case">IDH</jats:styled-content>1/2 or mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>1. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 bound to both <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, with Q316 being the critical residue mediating the binding of <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 with <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q, but not with <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 also had favorable pharmacokinetic characteristics and profoundly inhibited 2‐<jats:styled-content style="fixed-case">HG</jats:styled-content> production in a tumor xenografts model. The results of the current study establish a solid foundation for further clinical investigation of <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310, and provide new insight into the development of novel mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 inhibitors.</jats:p> |
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| spelling | Gao, Mingzhao Zhu, Hongmei Fu, Li Li, Yun Bao, Xubin Fu, Haoyu Quan, Haitian Wang, Lei Lou, Liguang 1347-9032 1349-7006 Wiley Cancer Research Oncology General Medicine http://dx.doi.org/10.1111/cas.14152 <jats:title>Abstract</jats:title><jats:p>Isocitrate dehydrogenase 2 (<jats:styled-content style="fixed-case">IDH</jats:styled-content>2), an important mitochondrial metabolic enzyme involved in the tricarboxylic acid cycle, is mutated in a variety of cancers. <jats:styled-content style="fixed-case">AG</jats:styled-content>‐221, an inhibitor primarily targeting the <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q mutant, has shown remarkable clinical benefits in the treatment of relapsed or refractory acute myeloid leukemia patients. However, <jats:styled-content style="fixed-case">AG</jats:styled-content>‐221 has weak inhibitory activity toward <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, a mutant form of <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 with more severe clinical manifestations. Herein, we report <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 as the first mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 inhibitor that potently targets both <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K mutants. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 inhibited mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 enzymatic activity, suppressed (R)‐2‐hydroxyglutarate (2‐<jats:styled-content style="fixed-case">HG</jats:styled-content>) production and induced differentiation in cells expressing <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, but not in cells expressing wild‐type <jats:styled-content style="fixed-case">IDH</jats:styled-content>1/2 or mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>1. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 bound to both <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q and <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K, with Q316 being the critical residue mediating the binding of <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 with <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R140Q, but not with <jats:styled-content style="fixed-case">IDH</jats:styled-content>2‐R172K. <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310 also had favorable pharmacokinetic characteristics and profoundly inhibited 2‐<jats:styled-content style="fixed-case">HG</jats:styled-content> production in a tumor xenografts model. The results of the current study establish a solid foundation for further clinical investigation of <jats:styled-content style="fixed-case">TQ</jats:styled-content>05310, and provide new insight into the development of novel mutant <jats:styled-content style="fixed-case">IDH</jats:styled-content>2 inhibitors.</jats:p> Pharmacological characterization of <scp>TQ</scp>05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants Cancer Science |
| spellingShingle | Gao, Mingzhao, Zhu, Hongmei, Fu, Li, Li, Yun, Bao, Xubin, Fu, Haoyu, Quan, Haitian, Wang, Lei, Lou, Liguang, Cancer Science, Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants, Cancer Research, Oncology, General Medicine |
| title | Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| title_full | Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| title_fullStr | Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| title_full_unstemmed | Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| title_short | Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| title_sort | pharmacological characterization of <scp>tq</scp>05310, a potent inhibitor of isocitrate dehydrogenase 2 r140q and r172k mutants |
| title_unstemmed | Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants |
| topic | Cancer Research, Oncology, General Medicine |
| url | http://dx.doi.org/10.1111/cas.14152 |