Abstract:
Lung cancer is a leading cause of cancer deaths worldwide. Somatic mutations in tyrosine kinase receptors that causes aberrant signalling have been implicated in the development of lung cancer. Two such receptors, EGFR and FGFR kinases are directly involved in many cases of aggressive metastasis and drug resistance. The FGFR kinase family consists of four highly conserved receptor proteins (FGFR1 – FGFR4). FGFR pathways are the main cause of resistance to chemotherapy in non-small cell lung cancer patients, and 22% of them show over-expression of FGFR1. There are a number of small molecules in phase III clinical trials that target not only FGFR but also other kinases. A wide range of EGFR mutations are linked to lung cancer development in never-smokers or former smokers. The two most common mutations are exon 19 deletions and the point mutation L858R in exon 21. Many patients harbouring L858R acquire a secondary T790M mutation after treatment with gefitinib/erlotinib resulting in drug resistance. In the past few years AstraZeneca have developed drugs that target specific proteins, eg; AZD4547 (FGFR1 selective) and AZD9291 (selectivity for T790M/L858R EGFR). In an effort to design our own novel and selective inhibitors, we solved the structures of AZD4547 and AZD9291 in complex with FGFR and EGFR respectively. In both cases, the phosphate binding loop (P-loop) of the proteins forms an unusual “bent” structure wrapped closely around these inhibitors. We speculate that the ability of these compounds to induce P-loop closure is an important part of their respective selectivity mechanisms.