Novel Bruton&amp;#39;s tyrosine kinase inhibitors currently in development

D’Cruz, Osmond J.; Uckun, Fatih M.

doi:10.2147/ott.s33732

Cited by 21 publications

(12 citation statements)

References 122 publications

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“…BTK is a fundamental component of the B cell receptor signalling, through which it regulates many cellular processes, including differentiation and signalling 2 . Various types of leukaemia and lymphoma express abundant levels of active BTK 3 , 4 . Because of this, Ibrutinib, a small-molecule inhibitor of BTK that forms a covalent bond with BTK near the ATP binding site at cysteine 481 and blocks autophosphorylation 5 , has shown clinical efficiency against B cell malignancies 4 .…”

Section: Introductionmentioning

confidence: 99%

BTK modulates p73 activity to induce apoptosis independently of p53

2018

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Bruton’s tyrosine kinase (BTK) is a key component of B cell receptor signalling. Because of this, BTK plays an important role in cell proliferation and survival in various B cell malignancies. However, in certain contexts, BTK can also have tumour suppressor functions. We have previously shown that BTK activates the p53 transcriptional activity by binding to and phosphorylating p53, as well as acting on MDM2 to reduce its inhibitory effects. This results in increased p53 functions, including enhanced cell death. Here, we report that BTK can also induce cell death and increase responses to DNA damage independently of p53. This is concomitant to the induction of p21, PUMA and MDM2, which are classic target genes of the p53 family of proteins. Our results show that these p53-independent effects of BTK are mediated through p73. Similar to what we observed in the p53 pathway, BTK can upregulate p73 after DNA damage and induce expression of its target genes, suggesting that BTK is a modulator of p73 functions and in the absence of p53. This effect allows BTK to have pro-apoptotic functions independently of its effects on the p53 pathway and thus play an important role in the DNA damage-related induction of apoptosis in the absence of p53. This provides a novel role of BTK in tumour suppression and contributes to the understanding of its complex pleiotropic functions

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Section: Introductionmentioning

confidence: 99%

BTK modulates p73 activity to induce apoptosis independently of p53

2018

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“…4 Hsp90 inhibitors and other agents have been shown to potentiate the efficacy of BTK inhibitors and signaling pathway inhibitors such as those targeting JAK2. 8, 41 These studies have made development of a multi-targeted BTK inhibitor an attractive approach for more effectively treating BCR-mediated cancers. 42 …”

Section: Discussionmentioning

confidence: 99%

“…MNK is downstream of the RAF-MEK-ERK signaling pathway and controls the transcription factor eIF4E, which is also linked to the mTOR signaling pathway. 8 Therefore, combinatorial inhibition of BTK and MNK kinase activity seems a feasible way to obtain greater efficacy than individually.…”

Section: Discussionmentioning

confidence: 99%

“…5, 6, 7 Upon BCR activation, BTK kinase translocates to the membrane and gets phosphorylated by Src family kinases at Y551, followed by auto-phosphorylation at Y223, which in turn induces the activation of PLCγ and other signaling pathways, including PI3K/Akt/mTOR, Stat5 and NF-κB. 4, 8 Defective BTK function has been linked to a variety of B-cell malignances, such as Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Diffuse Large B-Cell Lymphoma (DLBCL), Waldenstrom macroglobulinemia (WM) and Multiple Myeloma (MM). 8 Pharmacological targeting of BTK kinase has led to the discovery of the kinase inhibitor ibrutinib (PCI-32765), which has been clinically investigated for activity against CLL, MCL, WM, ABC-DLBCL, and MM and recently received regulatory approval for MCL and CLL.…”

Section: Introductionmentioning

confidence: 99%

“…4, 8 Defective BTK function has been linked to a variety of B-cell malignances, such as Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Diffuse Large B-Cell Lymphoma (DLBCL), Waldenstrom macroglobulinemia (WM) and Multiple Myeloma (MM). 8 Pharmacological targeting of BTK kinase has led to the discovery of the kinase inhibitor ibrutinib (PCI-32765), which has been clinically investigated for activity against CLL, MCL, WM, ABC-DLBCL, and MM and recently received regulatory approval for MCL and CLL. 9, 10, 11, 12 Recently, PCI-32765 has also demonstrated beneficial effects in AML.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia

Wang

et al. 2015

Leukemia

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BTK kinase is a member of the TEC kinase family and is a key regulator of the B-cell Receptor (BCR)-mediated signaling pathway. It is important for B-cell maturation, proliferation, survival and metastasis. Pharmacological inhibition of BTK is clinically effective against a variety of B-cell malignances, such as MCL, CLL and AML. MNK kinase is one of the key downstream regulators in the RAF-MEK-ERK signaling pathway and controls protein synthesis via regulating the activity of eIF4E. Inhibition of MNK activity has shown moderate efficacy for AML cell lines proliferation. Through a structure-based drug design approach, we have discovered a selective and potent BTK/MNK dual kinase inhibitor (QL-X-138), which exhibits covalent binding to BTK and non-covalent binding to MNK. Compared to the BTK kinase inhibitor (PCI-32765) and the MNK kinase inhibitor (cercosporamide), QL-X-138 displays a stronger anti-proliferative effect against a variety of B-cell cancer cell lines, as well as AML and CLL primary patient cells. The agent can effectively arrest the growth of lymphoma and leukemia cells at the G0–G1 stage and can induce strong apoptotic cell death. These results demonstrated that simultaneous inhibition of BTK and MNK kinase activity might be a new therapeutic strategy for B-cell malignances.

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