Novel Bruton's tyrosine kinase inhibitors currently in development

Abstract

Bruton's tyrosine kinase (Btk) is intimately involved in multiple signal-transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. Btk is overexpressed and constitutively active in several B-lineage lymphoid malignancies. Btk has emerged as a new antiapoptotic molecular target for treatment of B-lineage leukemias and lymphomas. Preclinical and early clinical results indicate that Btk inhibitors may be useful in the treatment of leukemias and lymphomas.

Keywords: Btk; kinase inhibitors; leukemia; lymphoma; personalized therapy; tyrosine kinase.

Figure 1

Btk activates antiapoptotic pathways. Btk is an upstream regulator of multiple antiapoptotic pathways, including the PI3K-AKT pathway, STAT5 pathway, and NFκB pathway. BTK also blocks the Fas-mediated apoptosis. See text for further discussion and references. Abbreviations: Btk, Bruton’s tyrosine kinase; PI3K, phosphatidylinositol 3-kinase; BAD, B-cell lymphoma 2-associated death promoter; IKK, IκB kinase; DISC, death-inducing signaling complex; STAT, signal transducer and activator of transcription; NFκB, nuclear factor kappa B.

Figure 2

Chemical structures of Bruton’s tyrosine kinase inhibitors. Ibrutinib (PCI-32765) is a covalent inhibitor currently under phase II and III clinical development for B-cell malignancies. Note: LFM-AI3, GDC-0834, and dasatinib are noncovalent adenosine triphosphate-competitive Bruton’s tyrosine kinase inhibitors.