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
SMILES: O=C(NCC1(C2=NC(C3=CC=CC=C3)=CS2)CCOCC1)C4=CC=CC(C5=NOC(C(F)(F)F)=N5)=C4
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
Eidogen Sertanty Inc Provides Oncology
Knowledge Base (OKB): a Collection of Various Cancer Targets and Their
Inhibitors.
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References:
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.
