Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor

Wu, Jingjing; Zhang, Mingzhi; Liu, Delong

doi:10.1186/s13045-016-0250-9

Cited by 195 publications

(122 citation statements)

References 38 publications

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“…Rather, BTK and TEC mRNA expression levels were somewhat increased, compared with naive B cells, and were correlated. Although secondgeneration Btk inhibitors with promising efficacy profiles have been developed (37,38), it is expected that combination regimens will result in long-lasting responses, as they may overcome resistance. Indeed, combining ibrutinib with a PI3K or Akt pathway inhibitor was shown to have synergistic effects (36,(39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling

Bruijn

Rip

Ploeg

et al. 2017

The Journal of Immunology

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The Tec tyrosine kinase is expressed in many cell types, including hematopoietic cells, and is a member of the Tec kinase family that also includes Btk. Although the role of Btk in B cells has been extensively studied, the role of Tec kinase in B cells remains largely unclear. It was previously shown that Tec kinase has the ability to partly compensate for loss of Btk activity in B cell differentiation, although the underlying mechanism is unknown. In this study, we confirm that Tec kinase is not essential for normal B cell development when Btk is present, but we also found that Tec-deficient mature B cells showed increased activation, proliferation, and survival upon BCR stimulation, even in the presence of Btk. Whereas Tec deficiency did not affect phosphorylation of phospholipase Cγ or Ca2+ influx, it was associated with significantly increased activation of the intracellular Akt/S6 kinase signaling pathway upon BCR and CD40 stimulation. The increased S6 kinase phosphorylation in Tec-deficient B cells was dependent on Btk kinase activity, as ibrutinib treatment restored pS6 to wild-type levels, although Btk protein and phosphorylation levels were comparable to controls. In Tec-deficient mice in vivo, B cell responses to model Ags and humoral immunity upon influenza infection were enhanced. Moreover, aged mice lacking Tec kinase developed a mild autoimmune phenotype. Taken together, these data indicate that in mature B cells, Tec and Btk may compete for activation of the Akt signaling pathway, whereby the activating capacity of Btk is limited by the presence of Tec kinase.

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Section: Discussionmentioning

confidence: 99%

Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling

Bruijn

Rip

Ploeg

et al. 2017

The Journal of Immunology

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“…39,40 A phase 1b study of acalabrutinib with or without rituximab is ongoing for patients with relapsed FL (NCT02180711). These more selective inhibitors may improve the therapeutic index, perhaps making them a better option for first-line or low-tumor-burden FL studies in which low toxicity treatments are appealing.…”

Section: Bartlett Et Almentioning

confidence: 99%

Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial

Bartlett

Costello

LaPlant

et al. 2018

Blood

136

105

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“…In addition, multiple trials of ACP-196 on other hematological malignancies and solid tumors are underway [34]. …”

Section: Introductionmentioning

confidence: 99%

Second-generation inhibitors of Bruton tyrosine kinase

et al. 2016

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Bruton tyrosine kinase (BTK) is a critical effector molecule for B cell development and plays a major role in lymphoma genesis. Ibrutinib is the first-generation BTK inhibitor. Ibrutinib has off-target effects on EGFR, ITK, and Tec family kinases, which explains the untoward effects of ibrutinib. Resistance to ibrutinib was also reported. The C481S mutation in the BTK kinase domain was reported to be a major mechanism of resistance to ibrutinib. This review summarizes the clinical development of novel BTK inhibitors, , ONO/GS-4059, and BGB-3111.

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Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor

Cited by 195 publications

References 38 publications

Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling

Distinct and Overlapping Functions of TEC Kinase and BTK in B Cell Receptor Signaling

Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial

Second-generation inhibitors of Bruton tyrosine kinase

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