SAR insights into TET2 catalytic domain inhibition: Synthesis of 2-Hydroxy-4-Methylene-pentanedicarboxylates

• Published in: Bioorganic & medicinal chemistry Vol. 39; p. 116141
• Main Authors: Tiwari, Anand D., Guan, Yihong, Grabowski, Dale R., Maciejewski, Jaroslaw P., Jha, Babal K., Phillips, James G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-06-2021
• Subjects: 2-Hydroxyglutarate; Catalytic Domain - drug effects; Cell-Free System; Dicarboxylic Acids - chemical synthesis; Dicarboxylic Acids - chemistry; Dicarboxylic Acids - pharmacology; Dioxygenase; Dioxygenases - metabolism; DNA Methylation; DNA-Binding Proteins - metabolism; Enzyme inhibition; Epigenetic; Humans; Molecular Docking Simulation; Spectrum Analysis - methods; Structure-Activity Relationship; TET; THP-1 Cells; α-KG; TET; D; Ddd; DMSO; 2-Hydroxyglutarate; MeCN; 5caC; J; Epigenetic; br s; 5hmC; dt; DIPEA. N; BSA; 5fC; LiOH; CHIP; THF; min; α-KG; TDG; DMAP; IDT; HPLC; Fe; Dd; EtOAc; PBS; Dioxygenase; UV; NOG; h; TBST; 5mC; ppm; EDTA; m; q; NMR; br m; t; DNA; HEPES; Enzyme inhibition; br d; ELISA
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2021.116141

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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 IC50 = 11.0 ± 0.9 μM at 10 μM α-KG in a cell free system and binds in the TET2 catalytic domain with Kd = 0.3 ± 0.12 μM.