Small molecule designed to block two key cancer enzymes simultaneously
US chemists have made a small molecule that simultaneously blocks two key enzymes involved in the growth of cancer cells. The dual inhibitor could prove more effective than traditional anti-cancer drugs, the researchers hope - and their rational design approach could lead to the pinpointing of other promiscuous compounds.
Kevan Shokat, of the University of California at Berkeley, and colleagues synthesised and screened hundreds of compounds to find one that could block two distinct kinases - enzymes involved in cell signalling pathways whose mutations are involved in many types of cancer.
Because cell signalling pathways are complex, taking one kinase out of a network is often not sufficient to stop cells growing: a cell can, in effect, reprogramme its signalling to find an alternative route around the blockage. Setting up two roadblocks simultaneously on separate parts of the network could prove much more damaging - but enzymes are highly specific, so to design a single molecule that will inhibit two different enzymes is a tall order.
The team knew that a particular molecule, a pyrazolopyrimidine, was an effective inhibitor of a tyrosine (protein) kinase. ’We already had 300 analogues of the molecule in the lab, and we screened these against the protein kinase and a phosphoinositide (lipid) kinase,’ says Shokat. ’Of these we found two that showed activity against both.’ To obtain more potent inhibition the researchers tweaked the molecule’s structure and synthesised over 200 more analogues, testing each for its effect.
The researchers homed in on one pyrazolopyrimidine, PP121, which showed high affinity to both enzymes.
’The key to the dual inhibition is that the inhibitor molecule can flex around a single bond that connects two ring systems,’ explains Shokat. The inhibitor is able to change its shape slightly, enabling it to occupy a binding pocket in both enzymes. PP121 is now undergoing tests to see if it might ultimately become an effective anti-cancer drug.
’Previously when drugs have been shown to hit multiple targets it has been serendipitous,’ comments Joanna Peak of the charity Cancer Research UK. ’What this work shows is that it is possible to take a rational approach to designing compounds to do this. A lot of medicinal chemists will be excited and encouraged by this paper.’
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B Apsel et al, Nature Chem. Biol., 2008, DOI: 10.1038/nchembio.117