Considerable biological evidence has accumulated in support of nominating the Class I PI3Ks (phosphoinositide 3-kinases) as excellent targets for the development of novel pharmaceuticals to treat cancer and inflammatory disease. Although it remains a goal to deliver compounds with precise PI3K isoform selectivity in order to minimize safety risks, it is not yet certain that this approach will deliver suitable benefit against disease when tested in the clinic. The UCB strategy, therefore, has been to generate a range of compounds covering a broad spectrum of PI3K isoform inhibition. Scaffold diversity has been accomplished by identifying hits using both pharmacophore search and high-throughput screening campaigns, while modulation of potency and isoform selectivity has been achieved through exploratory medicinal chemistry. Simple, high-throughput cell assays relevant to either inflammation or cancer have then been employed to establish a blueprint for defining how isoform selectivity affects biological potency. I will focus on two compounds from our collection: a pan-PI3K inhibitor and UCB1311236, a compound with significant potency against only the PI3Kγ isoform. These examples will be used to illustrate the extent to which isoform selectivity informs on compound potency against other kinases and to highlight the risks and benefits of developing compounds with limited isoform selectivity.
Conference Article| March 20 2007
Exploring the potential of PI3K inhibitors for inflammation and cancer
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T. Crabbe; Exploring the potential of PI3K inhibitors for inflammation and cancer. Biochem Soc Trans 1 April 2007; 35 (2): 253–256. doi: https://doi.org/10.1042/BST0350253
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