Thursday, April 17, 2014
European teams have pinpointed the DNA-protective enzyme 7,8-dihydro-8-oxoguanine triphosphatase as a chemically
tractable target whose inhibition kills cancer cells by accelerating DNA
damage.1,2 Both groups have identified collections of small molecule
inhibitors of the enzyme-one of which is an isomer of cancer drug Xalkori crizotinib-and both are
looking to partner with industry.
A team led by Giulio Superti-Furga did not set out to
interrogate MTH1 at all and came upon it while attempting to determine the
target of a 15-year-old compound that had been synthesized by
Schering-Plough Corp., SCH51344.
The CeMM lab began screening for inhibitors of MTH1 in
collaboration with Stefan Knapp, a professor of structural biology at the University of Oxford and principal investigator of epigenetics and chemical biology at the Structural Genomics Consortium. The hypothesis was that existing kinase
inhibitors, which often mimic ATP and thus are structurally related to MTH1's
nucleotide substrates, might also act on the target.
Both teams are continuing to synthesize and optimize
MTH1 inhibitors and are seeking development partners.
Cain, C. SciBX 7(15);
Published online April 17, 2014
1. Gad, H. et
al. Nature; published online April 2, 2014; doi:10.1038/nature13181
Contact: Thomas Helleday, Karolinska Institute, Stockholm,
2. Huber, K.V.M. et al. Nature; published online April 2,
Contact: Giulio Superti-Furga, Research Center for Molecular
Medicine of the Austrian Academy of Sciences, Vienna, Austria
3. Rai, P. et al. Oncogene 30,1489-1496 (2011)
4. Svensson, L.M. et al. FEBS Lett. 585, 2617-2621 (2011)
AND INSTITUTIONS MENTIONED
GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.
Karolinska Institute, Stockholm, Sweden
Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J.
Pfizer Inc. (NYSE:PFE), New York,
Research Center for Molecular Medicine of the Austrian
Academy of Sciences, Vienna,
Structural Genomics Consortium, Oxford, U.K.
University of Oxford, Oxford, U.K.