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TMP269 is a highly potent, selective and cell-permeable class IIa HDAC inhibitor with IC₅₀ of 126 nM, 80 nM, 36 nM and 19 nM for HDAC4, HDAC5, HDAC7 and HDAC9 respectively. It has very weak or no activity targeting the other HDACs (2-40 μM). TMP269 has an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. Crystallography revealed a direct metal binding of the TFMO, and the chemo-proteomics approach demonstrated the superior selectivity of TMP269 relative to the other hydroxamate-substituted analogs via a chelating zinc-binding group. TMP269 alters gene expression unlike class I and IIb HDAC inhibitors and affects colony-stimulating factor responses. The discovery of TMP269 provides an alternative design for targeting metalloenzymes than the conventional chelating metal-binding group, and suggests a therapeutic potential for class IIa HDAC inhibitors that are distinct in mechanism and application compared to current HDAC inhibitors.

How to Use:

• In vitro: TMP269 was suggested to be used at 3 μM final concentration in vitro and in cellular assays.
• In vivo: n/a

Reference:

1. 1. Lobera M, et al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. (2013) Nat Chem Biol. 9(5):319-25.

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