Project ID: TECH-2023-25
Background
Histone Deacetylases (HDACs) have been studied extensively for their role in regulating expression of genes and proteins involved in cancer cell proliferation and migration. The Zinc Binding Group (ZBG) is an essential component of the HDAC inhibitor pharmacophore. It binds to the zinc ion in the enzyme active site and inhibits the enzyme. Three of the four HDAC inhibitors approved by the FDA have hydroxamic acid as the ZBG. However, hydroxamates have poor pharmacokinetic properties and the hydroxamatic acid is a highly promiscuous metal-binding group which contributes to lack of selectivity and toxicity of hydroxamate HDAC inhibitors. Among the alternative ZBGs that have been explored, trifluoromethylketones (TFMKs) in the hydrated form had potent HDAC inhibitory and improved anti-tumor activity. Unfortunately, TFMK group is rapidly metabolized in vivo to an inactive alcohol form, with a half-life of 30 minutes.
Invention Description
Researchers at the University of Toledo have identified trifluoromethylpyruvamide (TFMP) as a metabolically more stable surrogate of TFMK. Incorporation of an additional electron-withdrawing group made the hydrate more stable and resistant to metabolic reduction. Further, it eliminates the potential of TFMK to act as PAINS. The TFMP analogues synthesized had both potent and selective HDAC inhibitory and cytotoxic activity. Preliminary isoform selectivity studies indicate that these compounds are more selective for HDAC8.
Applications
Treatment of cancer
Advantages
Publication: B. Riddhidev et al. Rational Design of Metabolically Stable HDAC Inhibitors: An Overhaul of Trifluoromethyl Ketones European Journal of Medicinal Chemistry 244 (2022) 114807
IP Status: Patent Pending