Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China
| Autor: | Shengtao Yuan, Han Luwei, Dezhen Peng, Zhiqiang Wang, Hongzhi Du, Li Sun, Zhang Xian, Zhao Liwen, Danyu Du, Ligong Lu, Meixiao Zhan, Zhibo Zhang, Yong Li |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
BCRP
breast cancer resistance protein Metabolite OATP organic anion transporting polypeptide IC50 half maximal inhibitory concentration Preclinical efficacy Papp apparent permeability coefficient chemistry.chemical_compound 0302 clinical medicine LC–MS/MS liquid chromatography–tandem mass spectrometry Medicine PDX patient-derived tumor xenograft General Pharmacology Toxicology and Pharmaceutics AML acute myeloid leukemia MDR1 multidrug resistance protein 1 media_common 0303 health sciences α-KG α-ketoglutaric acid mIDH2 inhibitor 2-Hydroxyglutarate ADME absorption distribution metabolism and excretion 030220 oncology & carcinogenesis Differentiation CYP cytochrome P450 Original Article Drug 2-HG 2-hydroxyglutaric acid Mutant isocitrate dehydrogenase 2 (mIDH2) media_common.quotation_subject CDX cell-line-derived xenograft RM1-950 IDH2 Acute myeloid leukaemia 03 medical and health sciences mIDH2 mutant isocitrate dehydrogenase Pharmacokinetics SH1573 AUC area under the cure AG-221 enasidenib Tumor metabolism Carcinogen 030304 developmental biology PD pharamacodynamics business.industry OCT organ cation transporter Clinical trial chemistry Cell culture Pharmacodynamics Cancer research OAT organic anion transporter PK pharmacokinetics Therapeutics. Pharmacology business EPO erythropoietin |
| Zdroj: | Acta Pharmaceutica Sinica B, Vol 11, Iss 6, Pp 1526-1540 (2021) Acta Pharmaceutica Sinica. B |
| ISSN: | 2211-3835 |
| Popis: | 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. Graphical abstract This study comprehensively evaluated SH1573, a novel mIDH2 inhibitor, in terms of pharmacodynamics, pharmacokinetics, and toxicological properties, which made this drug enter into the phase I clinical trials successfully.Image 1 |
| Databáze: | OpenAIRE |
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