Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China.
Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China.
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新型突变IDH2抑制剂SH1573在中国获批临床试验，对急性髓系白血病的临床前疗效
DOI：
10.1016/j.apsb.2021.03.005
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Zhan M
中科院分区：
文献类型：
--
作者：
Wang Z;Zhang Z;Li Y;Sun L;Peng D;Du D;Zhang X;Han L;Zhao L;Lu L;Du H;Yuan S;Zhan M
急性髓系白血病（AML）是成人中最常见的急性白血病，发病率随着年龄的增长而增加，预后通常较差。近20%的AML患者表达突变异柠檬酸脱氢酶2（mIDH2），导致致癌代谢物2-羟基戊二酸（2-HG）积累，导致预后不良。因此，全球机构一直致力于开发 mIDH2 抑制剂。 SH1573是我们自主设计合成的新型mIDH2抑制剂。我们对其药效学、药代动力学和安全性进行了全面的研究。首先，SH1573对mIDH2 R140Q蛋白表现出强烈的选择性抑制作用，可以有效减少动物模型的细胞系、血清和肿瘤中2-HG的产生。它还可以促进 PDX 模型中突变 AML 细胞系和粒细胞的分化。证实SH1573具有生物利用度高、代谢稳定性好、组织分布广的特点。最后，毒理学数据表明SH1573对呼吸系统、心血管系统和神经系统没有影响，基因安全。该研究成功推动SH1573获批临床试验（CTR20200247）。所有实验均表明，SH1573作为抗mIDH2 R140Q急性髓系白血病的潜在药物是有效且安全的。该研究对新型mIDH2抑制剂SH1573的药效学、药代动力学和毒理学特性进行了综合评价，使该药物成功进入I期临床试验。
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. 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.
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影响因子：
14.8
作者：
Gadhoum, Samah Zeineb;Sackstein, Robert
通讯作者：
Sackstein, Robert
影响因子：
11.4
作者：
Chou, W-C;Lei, W-C;Tien, H-F
通讯作者：
Tien, H-F
影响因子：
28.5
作者：
Her Z;Yong KSM;Paramasivam K;Tan WWS;Chan XY;Tan SY;Liu M;Fan Y;Linn YC;Hui KM;Surana U;Chen Q
通讯作者：
Chen Q
DOI：
10.1016/0006-291x(91)91647-u
发表时间：
1991-03-29
影响因子：
3.1
作者：
ARTURSSON, P;KARLSSON, J
通讯作者：
KARLSSON, J
影响因子：
64.8
作者：
Intlekofer AM;Shih AH;Wang B;Nazir A;Rustenburg AS;Albanese SK;Patel M;Famulare C;Correa FM;Takemoto N;Durani V;Liu H;Taylor J;Farnoud N;Papaemmanuil E;Cross JR;Tallman MS;Arcila ME;Roshal M;Petsko GA;Wu B;Choe S;Konteatis ZD;Biller SA;Chodera JD;Thompson CB;Levine RL;Stein EM
通讯作者：
Stein EM