Cancer Research UK Edinburgh Centre

Development of new inhibitors of oncogenic receptor tyrosine kinases

Cancer Research UK Edinburgh Centre scientists use cutting-edge approaches to develop novel inhibitors of oncogenic kinases: May 2018

Novel inhibitors of oncogenic kinases
Graphical abstract of the work published in the “Journal of Medicinal Chemistry” by the Innovative Therapeutics team and colleagues.

The costs of new drug development are continuously increasing, with $1.4 billion (= over £1 billion) being estimated as an average expense associated with bringing a new drug into the market. In response to this challenging situation, researchers are exploring new alternatives to target-based drug-development approaches typically employed by pharmaceutical companies in the hope of accelerating the earlier stages of the drug discovery process and reducing the overall drug development costs.

The Innovative Therapeutics lab led by Professor Asier Unciti-Broceta at the Cancer Research UK Edinburgh Centre is at the forefront of cutting-edge drug-development and drug-delivery technologies. Together with their collaborators, including Professor Val Brunton and her Cancer Therapeutics Group, they employ phenotypic screening and other state-of-the-art alternative drug discovery approaches to develop potential novel cancer therapeutics in an efficient way and at highly reduced costs.

In a recent study entitled “Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening” that has been published in the “Journal of Medicinal Chemistry” the group used an adaptive strategy that applies ligand-based design and phenotypic screening iteratively, and is informed by biochemical assays, to develop new lead compounds with unique selectivity profiles, including selective AXL inhibitors and a highly potent inhibitor of FLT3.

AXL and FLT3 are receptor tyrosine kinases that transduce extracellular signals into the cytoplasm and regulate many physiological processes including cell survival, cell proliferation, migration and differentiation. Both kinases have been implicated in oncogenesis and recognised as potential targets in cancer therapy, however there is a distinct lack of specific and highly potent inhibitors of both AXL and FLT3. The study by Professor Unciti-Broceta and colleagues represents an important step in development of such inhibitors and the compounds they described represent attractive leads for future optimization. Importantly, they displayed strong antiproliferative activity against cancer cells in cell culture in vitro.   

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