Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

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 IC 50 = 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.

Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro

“…Figure 1 shows the structures of some known inhibitors of the TNKSs. XAV939 1 7 and GM244-LM 2 35 both bind at the nicotinamide-binding site, as do our 2-arylquinazolin-4-ones 3 36,37 and flavones, including 4. 38,39 Our lead water-soluble inhibitor of PARP-1 and PARP-2, 5-AIQ 11a, [40][41][42][43][44] binds only weakly to the TNKSs, with IC 50 in the low lM range (preliminary data not shown).…”

“…The SAR from our preliminary study 36 on the 2-arylquinazolin-4-ones suggested that the lactam H-bonding motif was essential and that a para-substituted benzene ring could be accepted by the hydrophobic cavity. One example, (3: R 4 0 = CH 2 NHCbz, R 8 = Me) projected deep into the tunnel, with only slight loss of activity.…”

“…Secondly, the structure of XAV939 1 bound into the catalytic domain of TNKS-2 is available. 53 Thirdly, we sought to investigate 'scaffold-hopping' from our 2-arylquinazolin-4-one inhibitors, from our preliminary studies, 36 to the 3-arylisoquinolin-1-ones. into the NAD + -binding site, mimicking nicotinamide.…”

“…All carry a 5-substituent, as this was better in the quinazolin-4-ones. 36 However, the nature of the 5-substituent was not clearly predicted and comparison of compounds in the series 12-16 may clarify this. Compounds 12 and 16 have H-bond-donor electron-donating groups (EDGs) (the 5-NH 2 in 12 is unprotonated at physiological pH), whereas 15 contain a H-bond-acceptor EDG.…”

“…The preliminary SAR in the quinazolin-4-one series 36 and the crystal structures used here gave limited predictive information on the precise dimensions and the flexibility of the hydrophobic cavity; thus we tested these with the greater steric bulk of 12n, 13c,i,q, 15h and, in extremis, by the ferrocene in 13s. The dimensions were also tested by inserting a CH 2 CH 2 spacer between the isoquinolinone and the phenyl ring in 12s.…”