Towards Selective Inhibitors of FGFR Kinases using a De Novo Design Approach

The discovery of anti-cancer therapeutics remains at the forefront of modern medical science with the most recent forecast estimating that one in two people in the UK will be diagnosed with some form of cancer within their lifetime. The advancement of healthcare and overall better quality of life of the public over the past 50 years has seen a gradual increase in life expectancy. People are living longer, and with this comes new complications, outlining the need for novel anti-cancer therapeutics. FGFR kinases are a sub-family of receptor tyrosine kinases that are involved in many cellular processes and aberrant signalling within this class is implicated in many cancers. Currently, several anti-cancer therapeutics are in clinical use for FGFR related cancers with some acting as selective FGFR inhibitors. There are currently no examples of molecules that exhibit sub type selectivity for the FGFRs, an attribute that may be clinically relevant for FGFR-related cancers exhibiting toxic side-effects upon treatment. This thesis describes an attempt to identify a new series of sub-type selective FGFR kinase inhibitors. De novo design was carried out on the ATP binding site of an existing FGFR1 crystal structure and a small molecular scaffold based upon an indazole nucleus was identified. Subsequent enhancement using structure-based drug design led to two fragment-based lead series that exhibited single digit micromolar potency against FGFR1-3. Further rounds of de novo design, synthesis and biological evaluation led to one series showing preferential inhibition of FGFR2 over FGFR1/3, exhibiting potencies in the nanomolar range. This selectivity preference could not be rationalised through docking studies and therefore work was conducted in order to crystallise the inhibitors in both FGFR1/2. Analysis of the binding poses of the inhibitors bound within FGFR1/2 outlined key structural differences that may provide insight into the observed selectivity preference for FGFR2. These crystal structures have allowed the design of selective inhibitors of FGFR2 of which work is ongoing. Finally, inhibitors were evaluated for efficacy in a cellular environment. A general drop in potency of inhibitors was observed when compared to the potency of the compounds against the enzymes which may be attributed to the poor cellular uptake of the compounds