Alterations in genomic DNA can be detrimental to the individual carrying the mutation. Mutations in the gene for Bruton's tyrosine kinase (BTK) have been found to cause a functional BTK null phenotype that results in defective B cell development and function, and ultimately leads to the primary immunodeficiency X-linked agammaglobulinemia (XLA). In addition to such spontaneously occurring mutations, it is widely known that mutations can also appear under drug pressure. Excessive BTK-dependent signaling through the B-cell receptor governs cell survival and trafficking that result in B-cell malignancies. The BTK inhibitor Imbruvica ® (ibrutinib) has shown efficacy in treating a range of lymphomas, but it is well documented that patients taking this drug can relapse, and a range of BTK mutations has been identified in these individuals. In this presentation we will discuss the genetic understanding of the role of BTK in immune diseases and malignancies. We will highlight how our studies of native and mutant forms of this kinase have impacted our medicinal chemistry efforts at Genentech targeting BTK.

Impact of genetic insights on the development of BTK inhibitors

251st National Meeting (2016)

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