Personal reflections on the early days of kinase inhibitor probes

The first protein kinases and their role in cell regulation were identified in the mid-1950s, but it was not until the 1980s that the first inhibitors of these enzymes were developed. More specific inhibitors that suppressed kinase activity at low nanomolar concentrations were described in the mid-1990s and their potential to treat cancers caused by kinase mutation became clear during the late 1990s. Over 100 protein and lipid kinase inhibitors have now been approved for clinical use during the 21st century with combined annual sales of over US$ 65 billion in 2024. They have not only transformed the clinical care of multiple malignancies but have also been exploited widely to identify physiological substrates and cellular functions of these enzymes. Here, I present some personal reflections on the early days of kinases and their inhibitors, give a few examples of how they were first exploited to dissect signal transduction pathways and explain how the first panels of protein kinases came to be established to facilitate the development of more specific kinase inhibitors.