A team of British and French researchers from the pharmaceutical company AstraZeneca claims to have discovered a new class of quinazoline-based compounds.

A team of British and French researchers from the pharmaceutical company AstraZeneca claims to have discovered a new class of quinazoline-based compounds that are effective inhibitors of tyrosine kinase c-Src. This enzyme has been implicated in the development and progression of a range of cancerous tumours and these inhibitors could therefore form the basis of a new type of anti-cancer drug.

Tyrosine kinases are enzymes that phosphorylate proteins at a tyrosine residue. They are present in most cells, but certain tyrosine kinases, such as c-Src, appear to be over-expressed in cancer cells. Increased c-Src activity has been detected in breast, ovarian and colon cancer, where it has been linked to enhanced tumour progression. Although c-Src is one of the most studied tyrosine kinases, no inhibitor has yet been commercially developed to target tumour growth.

Using high-throughput screening, the AstraZeneca researchers identified a compound belonging to the anilinoquinazoline family as the basis for a potential inhibitor. They then experimented with substituting some of the methoxy groups on the quinazoline with other side-chains, including morpholinoproxy, benzofuran, indole and benzodioxole, to see how that affected the pharmacodynamics.

They eventually discovered that aminobenzodioxole quinazolines demonstrated the optimum profile of c-Src inhibition, selectivity and cellular potency. Tests on rats showed that this compound successfully reduced tumour growth by over 90 per cent.

Jon Evans

References

J. Med. Chem., 2004, 47, 871