The central role of dysregulated kinase activity in the etiology of progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over the past 40 years. As a result, kinase inhibitors are today one of the most important classes of drugs. The FDA approved 73 small molecule kinase inhibitor drugs until September 2021, and additional inhibitors were approved by other regulatory agencies during that time. To complement the published literature on clinical kinase inhibitors, we have prepared a review that recaps this large data set into an accessible format for the medicinal chemistry community. Along with the therapeutic and pharmacological properties of each kinase inhibitor approved across the world until 2020, we provide the synthesis routes originally used during the discovery phase, many of which were only available in patent applications. In the last section, we also provide an update on kinase inhibitor drugs approved in 2021.

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Dimethylfumarate (DMF) inhibits signals transmitted by Rel proteins and is used for the treatment of inflammatory skin diseases such as psoriasis, but potential effects of DMF on tumor progression have yet not been analyzed. We show that DMF reduced melanoma growth and metastasis in severe combined immunodeficient mouse models. To identify targets of DMF action, we analyzed mRNA expression in DMF-treated melanomas by gene chip arrays. Using BiblioSphere software for data analysis, significantly regulated genes were mapped to Gene Ontology terms cell death, cell growth, and cell cycle. Indeed, we found that DMF inhibited proliferation of human melanoma cells A375 and M24met in vitro. The cell cycle was arrested at the G 2 -M boundary. Moreover, DMF was proapoptotic, as shown by cell cycle analysis and by Annexin V and Apo2.7 staining. These results were confirmed in vivo. DMF reduced proliferation rates of tumor cells as assessed by Ki-67 immunostaining and increased apoptosis as assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining. In conclusion, DMF is antiproliferative and proapoptotic and reduces melanoma growth and metastasis in animal models. (Cancer Res 2006; 66(24): 11888-96)

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