Success of First BTK Inhibitor Opens New Options in B-Cell Malignancies

Jane de Lartigue, PhD
Published: Monday, Mar 03, 2014

Key Elements of BTK Signaling

Key Elements of BTK Signaling

BCR indicates B-cell receptor; BTK, Bruton tyrosine kinase. Source: GeneCards,

A greater understanding of the molecular mechanisms underlying lymphoid malignancies has fostered the development of targeted therapies, including those aimed at B-cell signaling pathways. In the past few years, overwhelmingly positive results have been observed with small-molecule inhibitors of Bruton tyrosine kinase (BTK), a downstream component of B-cell antigen receptor (BCR) signaling.

BTK: A Key Conduit of BCR Signaling Pathways The proliferation, differentiation, and survival of the B cells of the immune system are controlled by biochemical signals transmitted via the BCR, an antigen-specific receptor protein found in the membrane of these cells. Binding of a specific antigen to the immunoglobulin component of the BCR triggers a cascade of downstream molecules to become activated. Among them is BTK, a nonreceptor tyrosine kinase that was originally discovered in the early 1950s by the American pediatrician Ogden C. Bruton, MD, who linked BTK to a rare X-linked immunodeficiency syndrome.

Emergence of Ibrutinib Among the earliest small-molecule inhibitors of BTK to be described was LFM-A13. This agent was widely used in preclinical studies, but mostly to further delineate the cellular role of BTK. Since the agent also inhibited polo-like kinase (PLK) and Janus kinase (JAK) 2, it has not progressed beyond this stage of development. Things really began to move forward in this field after Zhengying Pan, PhD, now at Peking University, and colleagues designed ibrutinib in the mid-2000s. The compound, formerly identified as PCI-32765, is a small molecule that irreversibly inhibits BTK enzymatic activity by covalently binding to cysteine- 481 in the tyrosine kinase domain.
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