A Small Molecule Inhibitor of Bruton’s Tyrosine Kinase Involved in B-Cell Signaling

Inhibitors of Bruton’s tyrosine kinase (BTK) are under development as potential therapies for various autoimmune diseases. In repeat-dose toxicity studies, small-molecule BTK inhibitors (BTKi) have been reported to cause a constellation of histologic effects at the pancreatic endocrine–exocrine interface in male rats; however, similar findings were not reported in other species. Since the BTKi-induced pancreatic effect is morphologically similar to well-documented spontaneous changes (predominantly characterized by insular/peri-insular hemorrhage, pigment deposition, chronic inflammation, and fibrosis) that are known to vary by rat strain, we investigated potential strain-dependent differences in the pancreatic effects of a small-molecule BTKi, LY3337641. Following 13 weeks of LY3337641 treatment, Crl:CD(SD) rats were most sensitive, Crl:WI(Han) rats were of intermediate sensitivity, and Hsd:SD rats were least sensitive. These strain differences appear to be related to differences in rate of weight gain across strains and sexes; however, a definitive mechanism was not determined. This study demonstrated that BTKi-induced pancreatic effects were highly dependent on rat strain and correlated with differences in the incidence and severity of the spontaneous background change. When considered with the lack of pancreas effects in nonrat species, these changes in rats are unlikely predictive of similar changes in humans administered a BTK inhibitor.

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Faculty Opinions recommendation of Bruton's tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1064714.518656 ◽

2007 ◽

Author(s):

Steve Ward

Keyword(s):

Cell Migration ◽

Tyrosine Kinase ◽

B Cell ◽

Bruton’S Tyrosine Kinase ◽

Bruton's Tyrosine Kinase

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Dual Inhibition of Bruton’s Tyrosine Kinase and Phosphoinositide-3-Kinase p110δas a Therapeutic Approach to Treat Non-Hodgkin’s B Cell Malignancies

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.116.238022 ◽

2017 ◽

Vol 361 (2) ◽

pp. 312-321 ◽

Cited By ~ 3

Author(s):

Jennifer Alfaro ◽

Felipe Pérez de Arce ◽

Sebastián Belmar ◽

Glenda Fuentealba ◽

Patricio Avila ◽

...

Keyword(s):

Tyrosine Kinase ◽

B Cell ◽

Therapeutic Approach ◽

Bruton’S Tyrosine Kinase ◽

B Cell Malignancies ◽

Bruton's Tyrosine Kinase ◽

Dual Inhibition ◽

Phosphoinositide 3 Kinase

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Bruton's tyrosine kinase inhibition in the treatment of preclinical models and multiple sclerosis

Current Pharmaceutical Design ◽

10.2174/1381612827666210701152934 ◽

2021 ◽

Vol 27 ◽

Author(s):

Anja Steinmaurer ◽

Isabella Wimmer ◽

Thomas Berger ◽

Paulus Stefan Rommer ◽

Johann Sellner

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

Tyrosine Kinase ◽

B Cell ◽

Bruton’S Tyrosine Kinase ◽

Cumulative Number ◽

Phase 2 ◽

Bruton's Tyrosine Kinase ◽

Relapsing Remitting

: Significant progress has been made in understanding the immunopathogenesis of multiple sclerosis (MS) over recent years. Successful clinical trials with CD20-depleting monoclonal antibodies have corroborated the fundamental role of B cells in the pathogenesis of MS and reinforced the notion that cells of the B cell lineage are an attractive treatment target. Therapeutic inhibition of Bruton's tyrosine kinase (BTK), an enzyme involved in B cell and myeloid cell activation and function, is regarded as a next-generation approach that aims to attenuate both errant innate and adaptive immune functions. Moreover, brain-penetrant BTK inhibitors may impact compartmentalized inflammation and neurodegeneration within the central nervous system by targeting brain-resident B cells and microglia, respectively. Preclinical studies in animal models of MS corroborated an impact of BTK inhibition on meningeal inflammation and cortical demyelination. Notably, BTK inhibition attenuated the antigen-presenting capacity of B cells and the generation of encephalitogenic T cells. Evobrutinib, a selective oral BTK inhibitor, has been tested recently in a phase 2 study of patients with relapsing-remitting MS. The study met the primary endpoint of a significantly reduced cumulative number of Gadolinium-enhancing lesions under treatment with evobrutinib compared to placebo treatment. Thus, the results of ongoing phase 2 and 3 studies with evobrutinib, fenobrutinib, and tolebrutinib in relapsing-remitting and progressive MS are eagerly awaited. This review article introduces the physiological role of BTK, summarizes the pre-clinical and trial evidence, and addresses the potential beneficial effects of BTK inhibition in MS.

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