A successful drug in the clinic is the final proof that modulation of a protein target yields benefits. The drug in question may have limitations, such as side-effects from off-target toxicity, dose limited efficacy and the such like. As such drug discovery program ‘restart’ with the aim of making a ‘gold-standard’ treatment, armed with a wealth of data and understanding from the clinic. These programs can be difficult and have protracted testing cascades as a large quantity of measurements are required to demonstrate superiority.
This paper is one of host of recent examples with the aim optimising for a specific mutation of the protein target and off-target effects. The selectivity is gained using the covalent binding group and off-target selectivity (IGFR) is achieved by a combination of groups, shown by some excellent matched pair analysis. This in itself is great medicinal chemistry, but the paper also describes some of the trials and tribulations of late LO and early pre-clinical, including a small amount of human PK data.
Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor
J. Med. Chem. 2014, 57, 20, 8249–8267
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