Patent Watch

January 6, 2014

Quinazolinedionecarboxylic acid derivatives are tankyrase inhibitors. R. M. Keenan, A. B. Miller, and D. Qin describe quinazolinedionecarboxylic acid derivatives represented generally by formula 1 or 2. The compounds are tankyrase inhibitors that may be useful for treating cancer, fibrosis, and other hyperproliferative diseases.

The tankyrases (TNKS1 and TNKS2) are members of the poly-ADP–ribose polymerase (PARP) family of enzymes that act via mono- or poly-ADP-ribosylation (parsylation) of substrate proteins. These enzymes play important roles in cellular processes such as DNA repair and Wnt signaling. Tankyrases are implicated in other processes such as the positive regulation of telomere length and lung fibrogenesis.

General formulas and representative examples of tankyrase inhibitors

Deregulation of the Wnt–β-catenin pathway is linked to cancer. Studies show a possible link between increased activation of canonical Wnt signaling and fibrogenesis. Pathologically activated canonical Wnt also is implicated in the pathogenesis of pulmonary, renal, dermal, and liver fibrosis; and it is linked to scarring after the myocardial fibrosis that accompanies muscular dystrophy.

Thus, the inhibition of tankyrase activity may have broad clinical utility. The use of tankyrase inhibitors such as the molecules reported by the inventors may provide a useful therapy for treating hyperproliferative disorders, including cancer and fibrosis.

The inventors describe the synthesis of 14 examples of formulas 1 and 2, including examples 3, 4, and 5. To assay the activities of these quinazolinedionecarboxylic acid derivatives, they used inhibition of human TNKS1 or TNKS2 fluorescence polarization (FP) activity and inhibition of human TNKS1 or TNKS2 homogenous time-resolved fluorescence (HTRF) activity, both in vitro. They found that the 14 examples are tankyrase inhibitors with pIC50 >6 in one or both types of TNKS assays. The data for examples 3, 4, and 5 are shown in the table.

Example TNKS1
FP, pIC50
TNKS2
FP, pIC50
TNKS1
HTRF, pIC50
TNKS2
HTRF, pIC50
3 8.1 7.1 7.5 7.7
4 8.2 7.1 7.3 7.7
5 -- -- 6.5 7.0

(GlaxoSmithKline [Wilmington, DE]. WIPO Publication 2013177349, Nov. 28, 2013; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.