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.
J. Med. Chem., 2004, 47, 871