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Vorasidenib

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Chemical Structure| 1644545-52-7 同义名 : AG-881
CAS号 : 1644545-52-7
货号 : A289383
分子式 : C14H13ClF6N6
纯度 : 99%+
分子量 : 414.737
MDL号 : MFCD31630835
存储条件：

粉末 Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(253.17 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • Dehydrogenase
描述 IDH (Isocitrate dehydrogenase) is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Recurrent mutations in IDH1 or IDH2 are prevalent in several cancers including glioma, acute myeloid leukemia (AML), cholangiocarcinoma and chondrosarcoma. Vorasidenib is a pan-IDH inhibitor with IC50 values of 31.9nM and 31.7nM for IDH1-R132H and IDH2-R140Q, respectively[6], which fully penetrates the blood-brain barrier and selectively inhibits mutant IDH protein and induce cell differentiation in in vitro and in vivo models[7]. It is a rapid-equilibrium inhibitor of mIDH1-R132H and mIDH2-R172K homodimer enzymes and is a slow-binding inhibitor of mIDH2-R140Q homodimer and wild type (wt) IDH1/mIDH1-R132H, wtIDH2/mIDH2-R140Q, and wtIDH2/mIDH2-R172K heterodimers. The IC50 range for 2-HG inhibition by AG-881 was 0.04-22 nM in cells expressing mIDH1-R132C, mIDH1-R132G, mIDH1-R132H, or mIDH1-R132S mutations and was 7-14nM and 130nM in cells expressing mIDH2-R140Q and mIDH2-R172K mutations, respectively. The treatment of these mIDH cell lines or primary human acute myeloid leukemia samples with AG-881 led to the onset of cellular differentiation[3]. It has been developed and is in early phase I testing for patients with IDH mutation-positive hematologic malignancies and solid tumors, including glioma[8].
作用机制 AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets. It allosterically inhibits IDH activity by incurring steric hindrance.[6]
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.41mL

0.48mL

0.24mL

12.06mL

2.41mL

1.21mL

24.11mL

4.82mL

2.41mL
参考文献

[1]Ma R, Yun CH, et al. Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2. Biochem Biophys Res Commun. 2018 Sep 18;503(4):2912-2917.

[2]Fujii T, Khawaja MR, et al. Targeting isocitrate dehydrogenase (IDH) in cancer. Discov Med. 2016 May;21(117):373-80.

[3] Abstract B126: AG-881, a brain penetrant, potent, pan-mutant IDH (mIDH) inhibitor for use in mIDH solid and hematologic malignancies

[4]Dang L, Yen K, et al. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol. 2016 Apr;27(4):599-608.

[5]Zakkula A, Dittakavi S, et al. Validated HPLC method for simultaneous quantification of mutant IDH1/2 inhibitors (enasidenib, ivosidenib and vorasidenib) in mouse plasma: Application to a pharmacokinetic study. Biomed Chromatogr. 2019 Nov;33(11):e4658.

[6]Ma R, Yun CH. Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2. Biochem Biophys Res Commun. 2018 Sep 18;503(4):2912-2917. doi: 10.1016/j.bbrc.2018.08.068. Epub 2018 Aug 18. PMID: 30131249.

[7]Fujii T, Khawaja MR, DiNardo CD, Atkins JT, Janku F. Targeting isocitrate dehydrogenase (IDH) in cancer. Discov Med. 2016 May;21(117):373-80. PMID: 27355333.

[8]Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol. 2016 Apr;27(4):599-608. doi: 10.1093/annonc/mdw013. PMID: 27005468.