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Tomoko Yasuhiro, Wako Sawada, Christian Klein, Ryohei Kozaki, Shingo Hotta, Toshio Yoshizawa
The activated B-cell diffuse large B-cell-like lymphoma (ABC-DLBCL) correlates with poor prognosis. The B-cell receptor signaling pathway is known to be dysregulated in NHL/CLL and given BTK is a downstream mediator of BCR signaling, BTK constitutes an interesting and obvious therapeutic target. Given the high potency and selectivity of the BTK inhibitor, ONO/GS-4059, it was hypothesized that, the anti-tumor activity of ONO/GS-4059 could be further enhanced by combining it with the anti-CD20 Abs, rituximab (RTX) or obinutuzumab (GA101)...
August 9, 2016: Leukemia & Lymphoma
Xianhui Wang, Jason Wong, Christopher J Sevinsky, Leila Kokabee, Faiza Khan, Yan Sun, Douglas S Conklin
We have reported that a novel isoform of BTK (BTK-C) expressed in breast cancer protects these cells from apoptosis. In this study, we show that recently developed inhibitors of BTK, such as ibrutinib (PCI-32765), AVL-292, and CGI-1746, reduce breast cancer cell survival and prevent drug-resistant clones from arising. Ibrutinib treatment impacts HER2(+) breast cancer cell viability at lower concentrations than the established breast cancer therapeutic lapatinib. In addition to inhibiting BTK, ibrutinib, but not AVL-292 and CGI-1746, efficiently blocks the activation of EGFR, HER2, ErbB3, and ErbB4...
September 2016: Molecular Cancer Therapeutics
Gayathri Natarajan, Cesar Terrazas, Steve Oghumu, Sanjay Varikuti, Jason A Dubovsky, John C Byrd, Abhay R Satoskar
Ibrutinib (PCI-32765) is an irreversible dual Btk/Itk inhibitor shown to be effective in treating several B cell malignancies. However, limited studies have been conducted to study the effect of this drug on myeloid cell function. Hence, we studied the effect of ibrutinib treatment on TLR-4 mediated activation of bone marrow derived dendritic cell culture (DCs). Upon ibrutinib treatment, LPS-treated DCs displayed lower synthesis of TNF-α and nitric oxide (NO) and higher induction of IL-6, TGF-β, IL-10 and IL-18...
2016: Oncoimmunology
Kazumi Hagiwara, Takashi Tokunaga, Hiroatsu Iida, Hirokazu Nagai
BACKGROUND: Bendamustine is effective in B-cell malignancies, including mantle cell lymphoma (MCL), alone and in combination with other agents. This study investigated the combination effect of bendamustine and the Bruton tyrosine kinase (BTK) inhibitor PCI-32765 on MCL cell death and the underlying mechanisms. MATERIALS AND METHODS: Cytotoxicity was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MIT) assay. Apoptosis was assessed by annexin V/propidium iodide staining and protein expression was analyzed by western blotting...
December 2015: Anticancer Research
Xixiang Li, Aoli Wang, Kailin Yu, Ziping Qi, Cheng Chen, Wenchao Wang, Chen Hu, Hong Wu, Jiaxin Wu, Zheng Zhao, Juan Liu, Fengming Zou, Li Wang, Beilei Wang, Wei Wang, Shanchun Zhang, Jing Liu, Qingsong Liu
FLT3-ITD mutant has been observed in about 30% of AML patients and extensively studied as a drug discovery target. On the basis of the structure of PCI-32765 (ibrutinib), a BTK kinase inhibitor that was recently reported to bear FLT3 kinase activity through a structure-guided drug design approach, we have discovered compound 18 (CHMFL-FLT3-122), which displayed an IC50 of 40 nM against FLT3 kinase and achieved selectivity over BTK kinase (over 10-fold). It significantly inhibited the proliferation of FLT3-ITD positive AML cancer cell lines MV4-11 (GI50 = 22 nM), MOLM13/14 (GI50 = 21 nM/42 nM)...
December 24, 2015: Journal of Medicinal Chemistry
Parviz Kokhaei, Farhad Jadidi-Niaragh, Abdolreza Sotoodeh Jahromi, Anders Osterborg, Håkan Mellstedt, Mohammad Hojjat-Farsangi
Targeted therapies have appeared as new treatment options for several disease types, including cancer and autoimmune disorders. Of several targets, tyrosine kinases (TKs) are among the most promising. Overexpression of TKs provides a target for novel therapeutic agents, including small molecule inhibitors of tyrosine kinases (TKI). Ibrutinib (PCI-32765) is a TKI of Bruton's tyrosine kinase (Btk), a key kinase of the B-cell receptor signaling pathway that plays a significant role in the proliferation, differentiation and survival of B cells...
2016: Journal of Drug Targeting
Davide Grisafi, Alessandra Maestro, Camilla Grumi, Ludovica Piazzoni, Giampaolo Tirone, Walter Fiore, Roberto Tessari, Valeria Gianardi, Milo Gatti, Francesca Tasca, Daniele Generali, Andrea Ravelli, Francesco Lanza, Francesco Scaglione
The activation of the B cell receptor (BCR) is nowadays known to play a primary role in the etiopathogenesis of a multitude of B cell malignancies, being one of the main factors responsible for the enhanced proliferation and survival of transformed cells. Thanks to the characterization and continuous discovery of the pathways driving B cell proliferation in consequence to BCR activation, it has been possible to develop a small molecule inhibitor specifically antagonizing the Bruton's tyrosine kinase (BTK), an enzyme located in an early strategic position within the whole pathway...
September 2015: Medical Oncology
Jan de Jong, Donna Skee, Joe Murphy, Juthamas Sukbuntherng, Peter Hellemans, Johan Smit, Ronald de Vries, Juhui James Jiao, Jan Snoeys, Erik Mannaert
Ibrutinib (PCI-32765), a potent covalent inhibitor of Bruton's tyrosine kinase, has shown efficacy against a variety of B-cell malignancies. Given the prominent role of CYP3A in ibrutinib metabolism, effect of coadministration of CYP3A perpetrators with ibrutinib was evaluated in healthy adults. Ibrutinib (120 mg [Study 1, fasted], 560 mg [studies 2 (fasted), and 3 (nonfasted)]) was given alone and with ketoconazole [Study 1; 400 mg q.d.], rifampin [Study 2; 600 mg q.d.], and grapefruit juice [GFJ, Study 3]...
August 2015: Pharmacology Research & Perspectives
H Wu, C Hu, A Wang, E L Weisberg, Y Chen, C-H Yun, W Wang, Y Liu, X Liu, B Tian, J Wang, Z Zhao, Y Liang, B Li, L Wang, B Wang, C Chen, S J Buhrlage, Z Qi, F Zou, A Nonami, Y Li, S M Fernandes, S Adamia, R M Stone, I A Galinsky, X Wang, G Yang, J D Griffin, J R Brown, M J Eck, J Liu, N S Gray, Q Liu
Bruton's tyrosine kinase (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 mantle cell lymphoma, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and activated B-cell-diffuse large B-cell lymphoma. 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...
January 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Minako Ito, Takashi Shichita, Masahiro Okada, Ritsuko Komine, Yoshiko Noguchi, Akihiko Yoshimura, Rimpei Morita
Inflammasome activation has been implicated in various inflammatory diseases including post-ischaemic inflammation after stroke. Inflammasomes mediate activation of caspase-1, which subsequently induces secretion of pro-inflammatory cytokines such as IL-1β and IL-18, as well as a form of cell death called pyroptosis. In this study, we report that Bruton's tyrosine kinase (BTK) is an essential component of the NLRP3 inflammasome, in which BTK physically interacts with ASC and NLRP3. Inhibition of BTK by pharmacological or genetic means severely impairs activation of the NLRP3 inflammasome...
2015: Nature Communications
Rossana Maffei, Stefania Fiorcari, Silvia Martinelli, Leonardo Potenza, Mario Luppi, Roberto Marasca
Tyrosine kinase inhibitors (TKIs) targeting signaling molecules downstream B cell receptor (BCR) are powerfully spreading in the therapeutic landscape of B cell lymphoproliferative disease, due to a manageable toxicity profile and encouraging clinical effectiveness. In particular, ibrutinib, previously called PCI-32765, is a potent inhibitor of Bruton tyrosine kinase (Btk), recently approved for the treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Moreover, idelalisib (formerly GS-1101 and CAL-101) is a selective reversible inhibitor of the p110δ isoform of phosphoinositol 3 kinase (PI3K) approved for the treatment of patients with relapsed follicular lymphoma (FL) and CLL...
2015: Journal of Hematology & Oncology
Kazumi Hagiwara, Shinji Kunishima, Hiroatsu Iida, Yasuhiko Miyata, Tomoki Naoe, Hirokazu Nagai
Mantle cell lymphoma (MCL) is a B cell malignancy characterized by aberrant expression of cyclin D1 due to a t(11;14) translocation. MCL is refractory to conventional chemotherapy, and treatment remains challenging. We investigated the efficacy of the histone deacetylase (HDAC) inhibitor vorinostat combined with one of several B-cell receptor (BCR) signaling inhibitors on MCL cell death and the underlying mechanisms, using MCL cell lines. The Bruton's tyrosine kinase inhibitor PCI-32765 and the spleen tyrosine kinase inhibitor R406 showed synergistic effects with vorinostat on growth inhibition...
July 2015: Apoptosis: An International Journal on Programmed Cell Death
Irene Guendel, Sergey Iordanskiy, Gavin C Sampey, Rachel Van Duyne, Valerie Calvert, Emanuel Petricoin, Mohammed Saifuddin, Kylene Kehn-Hall, Fatah Kashanchi
Many cellular cofactors have been documented to be critical for various stages of viral replication. Using high-throughput proteomic assays, we have previously identified Bruton's tyrosine kinase (BTK) as a host protein that was uniquely upregulated in the plasma membrane of human immunodeficiency virus (HIV-1)-infected T cells. Here, we have further characterized the BTK expression in HIV-1 infection and show that this cellular factor is specifically expressed in infected myeloid cells. Significant upregulation of the phosphorylated form of BTK was observed in infected cells...
June 2015: Journal of Neurovirology
Alex F Herrera, Eric D Jacobsen
Ibrutinib (PCI-32765)--a potent, covalent inhibitor of Bruton tyrosine kinase (BTK), an important kinase in the B-cell receptor signaling pathway--was recently approved by the FDA for the treatment of relapsed or refractory mantle cell lymphoma (MCL). The drug was granted accelerated approval based on the findings of an international, multicenter, single-arm phase II study that enrolled patients with relapsed or refractory MCL. In the study, ibrutinib (560 mg daily) was well tolerated as a single agent and resulted in an overall response rate of 68% and an estimated median response duration of 17...
November 1, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Qing Zhang, Bing Xia, Fulian Qu, Tian Yuan, Shanqi Guo, Weipeng Zhao, Qian Li, Hongliang Yang, Yafei Wang, Yizhuo Zhang
OBJECTIVE: To investigate the proliferation inhibitory role and mechanism of PI3Kδ inhibitor CAL-101 on multiple myeloma (MM) cells, and to provide new therapeutic options for MM treatment. METHODS: MM cell lines U266 and RPMI8226 cells were treated with various concentrations of CAL-101. MTT assay and CalcuSyn software were performed to determine the inhibitory effect of CAL-101 and the synergistic effect with PCI- 32765, SAHA (suberoylanilide hydroxamic acid), BTZ (Bortezomib) on MM cells...
October 2014: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Nicole Grabinski, Florian Ewald
Ibrutinib (formerly PCI-32765) is a specific, irreversible, and potent inhibitor of Burton's tyrosine kinase (BTK) developed for the treatment of several forms of blood cancer. It is now an FDA-approved drug marketed under the name Imbruvica(TM) (Pharmacyclics, Inc.) and successfully used as an orally administered second-line drug in the treatment of mantle cell lymphoma. Since BTK is predominantly expressed in hematopoietic cells, the sensitivity of solid tumor cells to Ibrutinib has not been analyzed. In this study, we determined the effect of Ibrutinib on breast cancer cells...
December 2014: Investigational New Drugs
Matthew S Davids, Jennifer R Brown
Ibrutinib (formerly PCI-32765) is a potent, covalent inhibitor of Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor that is critical for B-cell survival and proliferation. In preclinical studies, ibrutinib bound to Bruton's tyrosine kinase with high affinity, leading to inhibition of B-cell receptor signaling, decreased B-cell activation and induction of apoptosis. In clinical studies, ibrutinib has been well-tolerated and has demonstrated profound anti-tumor activity in a variety of hematologic malignancies, most notably chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), leading to US FDA approval for relapsed CLL and MCL...
May 2014: Future Oncology
Sabine Ponader, Jan A Burger
Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma...
June 10, 2014: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Mark-Alexander Schwarzbich, Matthias Witzens-Harig
Abnormal B-cell receptor (BCR) signaling is a key mechanism of disease progression in B-cell malignancy. Bruton's tyrosine kinase (BTK) has a pivotal role in BCR signaling. Ibrutinib (PCI-32765) is a novel agent which serves as a covalent irreversible inhibitor of BTK. It is characterized by high selectivity for BTK and high potency. Preliminary data from phase I and ongoing phase II trials have proven very promising so far. It suggests the substance has high efficacy in B-cell malignancies such as chronic lymphocytic leukemia (CLL); diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantel cell lymphoma (MCL), and multiple myeloma (MM) and is very well tolerable...
2014: Recent Results in Cancer Research
Mariela Sivina, Robert J Kreitman, Evgeny Arons, Farhad Ravandi, Jan A Burger
B cell receptor (BCR) signalling plays a critical role in the progression of several B-cell malignancies, but its role in hairy cell leukaemia (HCL) is ambiguous. Bruton tyrosine kinase (BTK), a key player in BCR signalling, as well as B cell migration and adhesion, can be targeted with ibrutinib, a selective, irreversible BTK inhibitor. We analysed BTK expression and function in HCL and analysed the effects of ibrutinib on HCL cells. We demonstrated uniform BTK protein expression in HCL cells. Ibrutinib significantly inhibited HCL proliferation and cell cycle progression...
July 2014: British Journal of Haematology
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