TMP269

• CAT Number: I001210
• CAS Number: 1314890-29-3
• Molecular Formula: C25H21F3N4O3S
• Molecular Weight: 514.52
• Purity: 98%
• Target: HDAC
• Solubility: DMSO: ≥ 41 mg/mL
• Storage: Store at -20°C
• IC50: 126/80/36/9 nM for HDAC 4/5/7/9
• InChI: InChI=1S/C25H21F3N4O3S/c26-25(27,28)22-31-20(32-35-22)17-7-4-8-18(13-17)21(33)29-15-24(9-11-34-12-10-24)23-30-19(14-36-23)16-5-2-1-3-6-16/h1-8,13-14H,9-12,15H2,(H,29,33)
• InChIKey: HORXBWNTEDOVKN-UHFFFAOYSA-N
• SMILES: O=C(NCC1(C2=NC(C3=CC=CC=C3)=CS2)CCOCC1)C4=CC=CC(C5=NOC(C(F)(F)F)=N5)=C4

TMP269(CAT: I001210) is a novel and selective class IIa histone deacetylase (HDAC) inhibitor. It exhibits inhibitory activity against HDAC 4, 5, 7, and 9 with IC50 values of 126, 80, 36, and 9 nM, respectively. TMP269 shows a significant selectivity of 20-400 fold over class I HDACs. HDACs are enzymes involved in the regulation of gene expression through the removal of acetyl groups from histone proteins, thereby affecting chromatin structure and gene transcription. By inhibiting specific HDAC isoforms, TMP269 may modulate gene expression patterns and potentially have therapeutic applications in various diseases, including cancer and neurological disorders.

Reference

[1]. Lobera M, et al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat Chem Biol. 2013 May;9(5):319-25. Abstract In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.