Metabolically stable HDAC inhibitors with trifluoromethylpyruvamide as metal-binding group

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

• Potent cytotoxicity (nanomolar IC₅₀s)
• More selective for cancer cells over normal cells
• Not susceptible to in vivo metabolic reduction
• Does not act as PAINS. Not susceptible to react with endogenous reactive nucleophiles
• Longer half-life than TFMK in metabolism studies (peak still present after 2 hours, compared to less than 15 minutes for TFMK)
• Less likely to cause off-target effects compared to TFMK
• Scalable synthesis

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