Thursday, April 18, 2013
Researchers from the University of Oslo and Roche's
unit have developed several selective inhibitors of tankyrases TNKS
two druggable targets in the otherwise hard-to-hit WNT
pathway.1,2 The University team's lead compound has been licensed to Odin Therapeutics A/S for colorectal cancer.
Krauss' team ran an SAR study to find
potent derivatives of an earlier 1,2,4-triazole compound made by his team that blocked the adenosine
binding pocket of TNKS and TNKS2. The best compound to emerge from the SAR
study, named G007-LK, had in vitro IC50 values of 46 nM for
TNKS and 25 nM for TNKS2. The molecule also inhibited tankyrase activity at a
comparable concentration in cell culture.
Twilight of the tumors
The biggest challenge to further
development of G007-LK is its tolerability profile. In healthy mice, the
compound blocked the regeneration of intestinal crypt cells, a normal process
that depends on WNT signaling.
Osherovich, L. SciBX 6(15); doi:10.1038/scibx.2013.353
Published online April 18, 2013
1. Voronkov, A. et al.
J. Med. Chem.; published online March 11, 2013; doi:10.1021/jm4000566
Contact: Stefan Krauss, Oslo University Hospital, Oslo, Norway
Contact: Jens P. Morth, same affiliation as above
Contact: Jo Waaler, same affiliation as above
2. Lau, T. et al.
Cancer Res.; published online March 28, 2013;
Contact: Mike Costa, Genentech Research & Early Development, South
San Francisco, Calif.
3. Huang, S.-M.A. et
al. Nature 461, 614-620 (2009)
AND INSTITUTIONS MENTIONED
Genentech Inc., South San Francisco, Calif.
Novartis AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland
Novartis Institutes for BioMedical Research, Basel, Switzerland
Odin Therapeutics A/S, Oslo, Norway
Oslo University Hospital, Oslo, Norway
(SIX:ROG; OTCQX:RHHBY), Basel, Switzerland
University of Oslo, Oslo, Norway