(2R)-Octyl-α-hydroxyglutarate ((2R)-Octyl-2-HG) is a cell-permeable modification of the D-isomer of 2-Hydroxyglutarate[1]. (2R)-Octyl-α-hydroxyglutarate is a membrane-permeable precursor of the oncometabolite (R)-2-hydroxyglutarate (R-2HG) produced in IDH1 mutant tumor cells[2]. (2R)-Octyl-α-hydroxyglutarate can act as a competitive inhibitor of α-ketoglutarate (α-KG)-dependent deoxygenase[3]. (2R)-Octyl-α-hydroxyglutarate can inhibit homology-directed repair (HDR) activity in IDH1/2 mutant cells[4].
In vitro, treatment of wild-type HCT116 cells with (2R)-Octyl-α-hydroxyglutarate (0-1000μM) for 10 days increased the sensitivity of the cells to poly(adenosine 5′-diphosphate ribose) polymerase (PARP) inhibitors[5]. Treatment of THP1 cells with (2R)-Octyl-α-hydroxyglutarate (300μM) for 7 days did not increase the level of (R)-2-hydroxyglutarate in the cells[6].
References:
[1] Reitman Z J, Duncan C G, Poteet E, et al. Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia[J]. Journal of Biological Chemistry, 2014, 289(34): 23318-23328.
[2] Kim G H, Choi S Y, Oh T I, et al. IDH1R132H causes resistance to HDAC inhibitors by increasing NANOG in glioblastoma cells[J]. International Journal of Molecular Sciences, 2019, 20(11): 2679.
[3] Wang X, Liu R, Qu X, et al. α-Ketoglutarate-activated NF-κB signaling promotes compensatory glucose uptake and brain tumor development[J]. Molecular cell, 2019, 76(1): 148-162. e7.
[4] Dow J, Krysztofiak A, Liu Y, et al. Vulnerability of IDH1-mutant cancers to histone deacetylase inhibition via orthogonal suppression of DNA repair[J]. Molecular Cancer Research, 2021, 19(12): 2057-2067.
[5] Sulkowski P L, Corso C D, Robinson N D, et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity[J]. Science translational medicine, 2017, 9(375): eaal2463.
[6] Bassal M A, Samaraweera S E, Lim K, et al. Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia[J]. Nature communications, 2022, 13(1): 2614.
(2R)-Octyl-α-hydroxyglutarate ((2R)-Octyl-2-HG)是2-Hydroxyglutarate的D型异构体的修饰物，具有细胞渗透性[1]。(2R)-Octyl-α-hydroxyglutarate是IDH1突变肿瘤细胞中产生的癌代谢物(R)-2-羟基戊二酸（R-2HG）的膜渗透性前体形式[2]。(2R)-Octyl-α-hydroxyglutarate能够用作α-酮戊二酸（α-KG）依赖性脱氧酶的竞争性抑制剂[3]。(2R)-Octyl-α-hydroxyglutarate能够抑制IDH1/2突变细胞中同源定向修复（HDR）活性[4]。
在体外，(2R)-Octyl-α-hydroxyglutarate（0-1000μM）处理野生型HCT116细胞10天，增加了细胞对聚（腺苷 5′-二磷酸核糖）聚合酶（PARP）抑制剂的敏感性[5]。(2R)-Octyl-α-hydroxyglutarate（300μM）处理THP1细胞7天，不会引起细胞中(R)-2-hydroxyglutarate水平升高[6]。