Sunday, May 31, 2015

Drugs in Clinical Pipeline: TMP269

TMP269 [N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide] is a potent, selective class IIa histone deacetylases (HDACs) inhibitor. Class IIa histone deacetylases (HDACs), including HDAC4, HDAC5, HDAC7, and HDAC9, are thought to regulate gene expression by interacting with various transcription factors to repress their transcriptional activity, but the precise mechanism of action of these proteins in signal transduction remains incompletely understood. TMP269 has an inhibitory profile  with IC50 of 157 nM, 97 nM, 43 nM and 23 nM for HDAC4, HDAC5, HDAC7 and HDAC9, respectively.

Normally HDAC inhibition chemistry is ruled by hydroxamates, but with TMP269 the researchers have claimed introduction of unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. Direct metal binding of the TFMO through crystallographic approaches and application of  chemoproteomics demonstarted the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog.

The activity of TMP269 is as follows:

IC50 (HDAC4 enzyme assay) = 157 nM
IC50 (HDAC5 enzyme assay) = 97 nM
IC50 (HDAC7 enzyme assay) = 43 nM
IC50 (HDAC9 enzyme assay) = 23 nM

Common Name: TMP269
Synonyms:  TMP269; TMP 269; TMP-269
IUPAC Name: N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide
CAS Number: 1314890-29-3
Mechanism of Action: HDAC Inhibitor; Class IIa HDAC Inhibitor; Histone Deacetylases Inhibitor
Indication: Various Cancers; Anti-tumor Therapy
Development Stage: Investigational
Company: Tempero Pharma/GlaxoSmithKline

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1. Lobera, M.; et. al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat Chem Biol 2013, 9(5), 319-325.