Abstract
Tankyrases (TNKSs) are poly(ADP-ribose)polymerases
(PARPs) that are overexpressed in several clinical cancers. They regulate
elongation of telomeres, regulate the Wnt system, and are essential for the
function of the mitotic spindle. A set of 2-arylquinazolin-4-ones has been
designed and identified as potent and selective TNKS inhibitors, some being
more potent and selective than the lead inhibitor XAV939, with IC50 = 3 nM
vs. TNKS-2. Methyl was preferred at the 8-position and modest bulk at the
4-position of the 2-phenyl group; electronic effects and H-bonding were
irrelevant, but charge in the 4′-substituent must be avoided. Molecular
modeling facilitated initial design of the compounds and rationalization of
the SAR of binding into the nicotinamide-binding site of the target enzymes. These compounds have potential for further
development into anticancer drugs.
(PARPs) that are overexpressed in several clinical cancers. They regulate
elongation of telomeres, regulate the Wnt system, and are essential for the
function of the mitotic spindle. A set of 2-arylquinazolin-4-ones has been
designed and identified as potent and selective TNKS inhibitors, some being
more potent and selective than the lead inhibitor XAV939, with IC50 = 3 nM
vs. TNKS-2. Methyl was preferred at the 8-position and modest bulk at the
4-position of the 2-phenyl group; electronic effects and H-bonding were
irrelevant, but charge in the 4′-substituent must be avoided. Molecular
modeling facilitated initial design of the compounds and rationalization of
the SAR of binding into the nicotinamide-binding site of the target enzymes. These compounds have potential for further
development into anticancer drugs.
| Original language | English |
|---|---|
| Pages (from-to) | 1173-1177 |
| Number of pages | 5 |
| Journal | ACS Medicinal Chemistry Letters |
| Volume | 4 |
| Issue number | 12 |
| Early online date | 15 Oct 2013 |
| DOIs | |
| Publication status | Published - 12 Dec 2013 |
