Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
Bioorg Med Chem. 2021 Jun 1;39:116141. doi: 10.1016/j.bmc.2021.116141. Epub 2021 Apr 20.
The TET (Ten-Eleven Translocation) dioxygenase enzyme family comprising 3 members, TET1-3, play key roles in DNA demethylation. These processes regulate transcription programs that determine cell lineage, survival, proliferation, and differentiation. The impetus for our investigations described here is derived from the need to develop illuminating small molecule probes for TET enzymes with cellular activity and specificity. The studies were done so in the context of the importance of TET2 in the hematopoietic system and the preponderance of loss of function somatic TET2 mutations in myeloid diseases. We have identified that 2-hydroxy-4-methylene-pentanedicarboxylic acid 2a reversibly competes with the co-substrate α-KG in the TET2 catalytic domain and inhibits the dioxygenase activity with an IC = 11.0 ± 0.9 μM at 10 μM α-KG in a cell free system and binds in the TET2 catalytic domain with K = 0.3 ± 0.12 μM.
TET（Ten-Eleven Translocation）双加氧酶家族由 3 个成员，TET1-3，在 DNA 去甲基化中发挥关键作用。这些过程调节转录程序，决定细胞谱系、存活、增殖和分化。我们在这里描述的研究动力来自于开发具有细胞活性和特异性的 TET 酶的小分子探针的需要。这些研究是在 TET2 在造血系统中的重要性以及髓系疾病中功能丧失性体细胞 TET2 突变的优势的背景下进行的。我们已经确定 2-羟基-4-亚甲基戊二酸 2a 可在 TET2 催化结构域中可逆地与共底物 α-KG 竞争，并在无细胞体系中在 10 μM α-KG 下以 11.0 ± 0.9 μM 的 IC 50 抑制双加氧酶活性，并且以 K = 0.3 ± 0.12 μM 的亲和力结合在 TET2 催化结构域中。
