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Progress in the Discovery of BCR-ABL Kinase Inhibitors for the Treatment of Leukemia

  • Chapter
Cancer II

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 28))

Abstract

Chemists first employed structure–activity relationships in designing busulphan, a chemotherapeutic for chronic myeloid leukemia (CML) in the 1950s. However, despite chemotherapy and later interferon immunotherapy, the median survival of patients remained less than 5 years. The elucidation that CML is driven by a tyrosine kinase mutation in haematopoietic stem cells enabled the discovery of imatinib, the first oncoprotein-targeted drug. Imatinib revolutionised CML therapy and set a new paradigm for the discovery of improved cancer drugs. Subsequently, medicinal chemists have capitalised upon X-ray co-crystal structures to rationally design superior ATP-competitive and allosteric ABL inhibitors. This progress has translated into clinical practice, such that chronic phase CML patients treated according to current guidelines have a normal life expectancy and many might in the future be able to discontinue treatment and maintain treatment-free remission. This review documents the history of CML drug discovery from arsenic through to asciminib, and progress towards a potential leukemia cure.

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    Paul W. Manley & Nikolaus J. Stiefl

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    Michael J. Waring

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Manley, P.W., Stiefl, N.J. (2017). Progress in the Discovery of BCR-ABL Kinase Inhibitors for the Treatment of Leukemia. In: Waring, M.J. (eds) Cancer II. Topics in Medicinal Chemistry, vol 28. Springer, Cham. https://doi.org/10.1007/7355_2017_5

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