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1.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209188

RESUMO

Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton's tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.


Assuntos
Adenina/análogos & derivados , Reposicionamento de Medicamentos , Simulação de Dinâmica Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/química , Pirazóis/química , Pirimidinas/química , Adenina/química , Adenina/metabolismo , Adenina/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Humanos , Simulação de Acoplamento Molecular , Piperidinas/metabolismo , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Termodinâmica , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo
2.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071917

RESUMO

Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones' hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton's Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones' interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Terapia de Alvo Molecular , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/química , Tirosina Quinase da Agamaglobulinemia/metabolismo , Biomarcadores Tumorais , Medula Óssea/metabolismo , Medula Óssea/patologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Relação Estrutura-Atividade , Microambiente Tumoral/efeitos dos fármacos
3.
Molecules ; 26(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062884

RESUMO

Osteoporosis is a systemic metabolic bone disorder that is caused by an imbalance in the functions of osteoclasts and osteoblasts and is characterized by excessive bone resorption by osteoclasts. Targeting osteoclast differentiation and bone resorption is considered a good fundamental solution for overcoming bone diseases. ß-boswellic acid (ßBA) is a natural compound found in Boswellia serrata, which is an active ingredient with anti-inflammatory, anti-rheumatic, and anti-cancer effects. Here, we explored the anti-resorptive effect of ßBA on osteoclastogenesis. ßBA significantly inhibited the formation of tartrate-resistant acid phosphatase-positive osteoclasts induced by receptor activator of nuclear factor-B ligand (RANKL) and suppressed bone resorption without any cytotoxicity. Interestingly, ßBA significantly inhibited the phosphorylation of IκB, Btk, and PLCγ2 and the degradation of IκB. Additionally, ßBA strongly inhibited the mRNA and protein expression of c-Fos and NFATc1 induced by RANKL and subsequently attenuated the expression of osteoclast marker genes, such as OC-STAMP, DC-STAMP, ß3-integrin, MMP9, ATP6v0d2, and CtsK. These results suggest that ßBA is a potential therapeutic candidate for the treatment of excessive osteoclast-induced bone diseases such as osteoporosis.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Reabsorção Óssea , Regulação da Expressão Gênica , Osteoclastos/metabolismo , Fosfolipase C gama/metabolismo , Ligante RANK , Triterpenos/farmacologia , Animais , Boswellia , Diferenciação Celular , Técnicas de Cocultura , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Fosforilação , Transdução de Sinais
4.
Clin Adv Hematol Oncol ; 19(6): 376-382, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34106911

RESUMO

Although chemotherapy has been a mainstay of the frontline treatment of mantle cell lymphoma (MCL) for many years, novel agents-including Bruton kinase inhibitors, immunomodulatory agents, and BCL2 inhibitors-have shown promise in patients with relapsed and refractory disease, and they are also being studied in the frontline setting. This review summarizes the current clinical data for using these novel agents in untreated MCL, both in combination with chemotherapy and singly, and discusses some of the trials currently under way to assess their future potential.


Assuntos
Antineoplásicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores
6.
Int J Mol Sci ; 22(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917250

RESUMO

Limiting bone resorption and regenerating bone tissue are treatment goals in myeloma bone disease (MMBD). Physical stimuli such as mechanical loading prevent bone destruction and enhance bone mass in the MOPC315.BM.Luc model of MMBD. It is unknown whether treatment with the Bruton's tyrosine kinase inhibitor CC-292 (spebrutinib), which regulates osteoclast differentiation and function, augments the anabolic effect of mechanical loading. CC-292 was administered alone and in combination with axial compressive tibial loading in the MOPC315.BM.Luc model for three weeks. However, neither CC-292 alone nor its use in combination with mechanical loading was more effective in reducing osteolytic bone disease or rescuing bone mass than mechanical stimuli alone, as evidenced by microcomputed tomography (microCT) and histomorphometric analysis. Further studies are needed to investigate novel anti-myeloma and anti-resorptive strategies in combination with physical stimuli to improve treatment of MMBD.


Assuntos
Acrilamidas/administração & dosagem , Doenças Ósseas/etiologia , Doenças Ósseas/prevenção & controle , Mieloma Múltiplo/complicações , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Estresse Mecânico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Doenças Ósseas/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Osteólise/etiologia , Osteólise/patologia , Osteólise/prevenção & controle , Microtomografia por Raio-X
7.
Biochem Biophys Res Commun ; 555: 196-201, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33831782

RESUMO

The nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) inflammasome is a critical inflammatory mechanism identified in platelets, which controls platelet activation and aggregation. We have recently shown that the platelet NLRP3 inflammasome is upregulated in sickle cell disease (SCD), which is mediated by Bruton tyrosine kinase (BTK). Here, we investigated the effect of pharmacological inhibition of NLRP3 and BTK on platelet aggregation and the formation of in vitro thrombi in Townes SCD mice. Mice were injected for 4 weeks with the NLRP3 inhibitor MCC950, the BTK inhibitor ibrutinib or vehicle control. NLRP3 activity, as monitored by caspase-1 activation, was upregulated in platelets from SCD mice, which was dependent on BTK. Large areas of platelet aggregates detected in the liver of SCD mice were decreased when mice were treated with MCC950 or ibrutinib. Moreover, platelet aggregation and in vitro thrombus formation were upregulated in SCD mice and were inhibited when mice were subjected to pharmacological inhibition of NLRP3 and BTK. Targeting the NLRP3 inflammasome might be a novel approach for antiplatelet therapy in SCD.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Anemia Falciforme/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Agregação Plaquetária/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Modelos Animais de Doenças , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamassomos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piperidinas/farmacologia , Agregação Plaquetária/fisiologia , Sulfonas/farmacologia , Trombose/tratamento farmacológico , Trombose/etiologia
8.
Int J Mol Sci ; 22(7)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801644

RESUMO

Therapeutically controlling chronic progression in multiple sclerosis (MS) remains a major challenge. MS progression is defined as a steady loss of parenchymal and functional integrity of the central nervous system (CNS), occurring independent of relapses or focal, magnetic resonance imaging (MRI)-detectable inflammatory lesions. While it clinically surfaces in primary or secondary progressive MS, it is assumed to be an integral component of MS from the very beginning. The exact mechanisms causing progression are still unknown, although evolving evidence suggests that they may substantially differ from those driving relapse biology. To date, progression is assumed to be caused by an interplay of CNS-resident cells and CNS-trapped hematopoietic cells. On the CNS-resident cell side, microglia that are phenotypically and functionally related to cells of the monocyte/macrophage lineage may play a key role. Microglia function is highly transformable. Depending on their molecular signature, microglia can trigger neurotoxic pathways leading to neurodegeneration, or alternatively exert important roles in promoting neuroprotection, downregulation of inflammation, and stimulation of repair. Accordingly, to understand and to possibly alter the role of microglial activation during MS disease progression may provide a unique opportunity for the development of suitable, more effective therapeutics. This review focuses on the current understanding of the role of microglia during disease progression of MS and discusses possible targets for therapeutic intervention.


Assuntos
Microglia/fisiologia , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/terapia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Progressão da Doença , Regulação para Baixo , Humanos , Inflamação , Lisofosfolipídeos/metabolismo , Macrófagos/metabolismo , Imageamento por Ressonância Magnética , Glicoproteínas de Membrana/metabolismo , Monócitos/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Fenótipo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores Imunológicos/metabolismo , Receptores Purinérgicos P2X/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo
10.
Front Immunol ; 12: 611656, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746955

RESUMO

Background: Psoriatic arthritis (PsA) is a chronic inflammatory joint disease within the spondyloarthritis spectrum. IL-12p40/IL-23p40 blockade reduces PsA disease activity, but its impact on synovial inflammation remains unclear. Objectives: To investigate the cellular and molecular pathways affected by IL-12p40/IL-23p40 blockade with ustekinumab in the synovium of PsA patients. Methods: Eleven PsA patients with at least one inflamed knee or ankle joint were included in a 24-week single-center open-label study and received ustekinumab 45 mg/sc according to standard care at week 0, 4, and 16. Besides clinical outcomes, synovial tissue (ST) samples were obtained by needle arthroscopy from an inflamed knee or ankle joint at baseline, week 12 and 24 and analyzed by immunohistochemistry, RNA-sequencing and real-time quantitative polymerase chain reaction (qPCR). Results: We obtained paired baseline and week 12, and paired baseline, week 12 and 24 ST samples from nine and six patients, respectively. Eight patients completed 24 weeks of clinical follow-up. At 12 weeks 6/11 patients met ACR20, 2/11 met ACR50 and 1/11 met ACR70 improvement criteria, at 24 weeks this was 3/8, 2/8 and 1/8 patients, respectively. Clinical and serological markers improved significantly. No serious adverse events occurred. We observed numerical decreases of all infiltrating cell subtypes at week 12, reaching statistical significance for CD68+ sublining macrophages. For some cell types this was even more pronounced at week 24, but clearly synovial inflammation was incompletely resolved. IL-17A and F, TNF, IL-6, IL-8, and IL-12p40 were not significantly downregulated in qPCR analysis of W12 total biopsies, only MMP3 and IL-23p19 were significantly decreased. RNA-seq analysis revealed 178 significantly differentially expressed genes between baseline and 12 weeks (FDR 0.1). Gene Ontology and KEGG terms enrichment analyses identified overrepresentation of biological processes as response to reactive oxygen species, chemotaxis, migration and angiogenesis as well as MAPK-ERK and PI3K-Akt signaling pathways among the downregulated genes and of Wnt signaling pathway among the upregulated genes. Furthermore, ACR20 responders and non-responders differed strikingly in gene expression profiles in a post-hoc exploratory analysis. Conclusions: Ustekinumab suppresses PsA synovial inflammation through modulation of multiple signal transduction pathways, including MAPK-ERK, Wnt and potentially PI3K-Akt signaling rather than by directly impacting the IL-17 pathway.


Assuntos
Subunidade p40 da Interleucina-12/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sinovite/metabolismo , Sinovite/patologia , Ustekinumab/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Tirosina Quinase da Agamaglobulinemia , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/etiologia , Artrite Psoriásica/metabolismo , Artrite Psoriásica/patologia , Biomarcadores , Biologia Computacional/métodos , Citocinas/metabolismo , Ontologia Genética , Humanos , Imuno-Histoquímica , Fosfatidilinositol 3-Quinases/metabolismo , Índice de Gravidade de Doença , Sinovite/tratamento farmacológico , Sinovite/etiologia , Transcriptoma , Ustekinumab/uso terapêutico
11.
Eur J Med Chem ; 217: 113329, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33740548

RESUMO

Therapy based on Bruton's tyrosine kinase (BTK) inhibitors one of the major treatment options currently recommended for lymphoma patients. The first generation of BTK inhibitor, Ibrutinib, achieved remarkable progress in the treatment of B-cell malignancies, but still has problems with drug-resistance or off-target induced serious side effects. Therefore, numerous new BTK inhibitors were developed to address this unmet medical need. In parallel, the effect of BTK inhibitors against immune-related diseases has been evaluated in clinical trials. This review summarizes recent progress in the research and development of BTK inhibitors, with a focus on structural characteristics and structure-activity relationships. The structure-refinement process of representative pharmacophores as well as their effects on binding affinity, biological activity and pharmacokinetics profiles were analyzed. The advantages and disadvantages of reversible/irreversible BTK inhibitors and their potential implications were discussed to provide a reference for the rational design and development of novel potent BTK inhibitors.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Desenvolvimento de Medicamentos , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
12.
Am J Physiol Cell Physiol ; 320(5): C902-C915, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33689480

RESUMO

Spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (BTK) play critical roles in platelet physiology, facilitating intracellular immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling downstream of platelet glycoprotein VI (GPVI) and GPIIb/IIIa receptors. Small molecule tyrosine kinase inhibitors (TKIs) targeting Syk and BTK have been developed as antineoplastic and anti-inflammatory therapeutics and have also gained interest as antiplatelet agents. Here, we investigate the effects of 12 different Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. These inhibitors include four Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659; four irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib), AVL-292 (spebrutinib); and four reversible BTK inhibitors, CG-806, BMS-935177, BMS-986195, and fenebrutinib. In vitro, TKIs targeting Syk or BTK reduced platelet adhesion to collagen, dense granule secretion, and alpha granule secretion in response to the GPVI agonist cross-linked collagen-related peptide (CRP-XL). Similarly, these TKIs reduced the percentage of activated integrin αIIbß3 on the platelet surface in response to CRP-XL, as determined by PAC-1 binding. Although all TKIs tested inhibited phospholipase C γ2 (PLCγ2) phosphorylation following GPVI-mediated activation, other downstream signaling events proximal to phosphoinositide 3-kinase (PI3K) and PKC were differentially affected. In addition, reversible BTK inhibitors had less pronounced effects on GPIIb/IIIa-mediated platelet spreading on fibrinogen and differentially altered the organization of PI3K around microtubules during platelets spreading on fibrinogen. Select TKIs also inhibited platelet aggregate formation on collagen under physiological flow conditions. Together, our results suggest that TKIs targeting Syk or BTK inhibit central platelet functional responses but may differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Plaquetas/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Glicoproteínas da Membrana de Plaquetas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinase Syk/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Plaquetas/enzimologia , Feminino , Humanos , Masculino , Terapia de Alvo Molecular , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Transdução de Sinais , Quinase Syk/metabolismo
13.
Blood Adv ; 5(3): 913-925, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33560402

RESUMO

Tyrosine kinase inhibitors (TKIs) are used to target dysregulated signaling pathways in virtually all hematologic malignancies. Many of the targeted signaling pathways are also essential in nonmalignant immune cells. The current coronavirus severe acute respiratory syndrome coronavirus 2 pandemic catalyzed clinical exploration of TKIs in the treatment of the various stages of COVID-19, which are characterized by distinct immune-related complications. Most of the reported effects of TKIs on immune regulation have been explored in vitro, with different class-specific drugs having nonoverlapping target affinities. Moreover, many of the reported in vivo effects are based on artificial animal models or on observations made in symptomatic patients with a hematologic malignancy who often already suffer from disturbed immune regulation. Based on in vitro and clinical observations, we attempt to decipher the impact of the main TKIs approved or in late-stage development for the treatment of hematological malignancies, including inhibitors of Bruton's tyrosine kinase, spleen tyrosine kinase, BCR-Abl, phosphatidylinositol 3-kinase/ mammalian target of rapamycin, JAK/STAT, and FMS-like tyrosine kinase 3, to provide a rationale for how such inhibitors could modify clinical courses of diseases, such as COVID-19.


Assuntos
Imunidade Adaptativa , COVID-19/patologia , Neoplasias Hematológicas/tratamento farmacológico , Imunidade Inata , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , COVID-19/complicações , COVID-19/imunologia , COVID-19/virologia , Citocinas/metabolismo , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/metabolismo , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/patologia , Humanos , SARS-CoV-2/isolamento & purificação
15.
Lancet Haematol ; 8(4): e254-e266, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33631112

RESUMO

BACKGROUND: Patients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population. METHODS: We did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2-6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02301156, and the final analysis is presented. FINDINGS: 224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n=64) or ibrutinib alone (n=62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7-47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p=0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related. INTERPRETATION: The addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients. FUNDING: TG Therapeutics.


Assuntos
Adenina/análogos & derivados , Anticorpos Monoclonais/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/uso terapêutico , Administração Intravenosa , Administração Oral , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Segurança , Resultado do Tratamento , Estados Unidos/epidemiologia
16.
Leukemia ; 35(5): 1317-1329, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33526860

RESUMO

Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the "gatekeeper" residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.


Assuntos
Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/genética , Benzamidas/farmacologia , Cisteína/genética , Resistencia a Medicamentos Antineoplásicos/genética , Mutação/genética , Piperidinas/farmacologia , Pirazinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Adenina/fisiologia , Animais , Células COS , Linhagem Celular , Linhagem Celular Tumoral , Galinhas , Chlorocebus aethiops , Células HEK293 , Humanos , Inibidores de Proteínas Quinases/farmacologia , Treonina/genética
17.
Blood Adv ; 5(1): 334-343, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33570649

RESUMO

Insight into the critical role of B-cell receptor signaling for the pathogenesis of chronic lymphocytic leukemia (CLL) led to the development of targeted therapies directed at key regulators of cell survival. Agents targeting B-cell lymphoma-2 protein, Bruton's tyrosine kinase (BTK), and phosphatidylinositol 3-kinase are approved for treatment of CLL, and have significantly improved the disease management. Nevertheless, acquired resistance to the targeted therapies is a challenge still to be resolved. The mechanisms underlying resistance are becoming clearer, and include secondary mutations within the drug target and activation of bypass pathways. This knowledge has allowed development of strategies to prevent and overcome treatment resistance. Approaches to prevent resistance include targeting bypass mechanisms by combination therapies, temporally sequencing of therapies, improved clinical trial designs, and real-time monitoring of patient response. A rational design of drug sequencing may secure effective treatment options at the relapsed setting. Next-generation inhibitors and bispecific antibodies have the potential to overcome resistance to the BTK inhibitor ibrutinib. Immunotherapy, including chimeric antigen receptor-modified T-cell therapy, is explored for relapsed CLL. Here, recent advances that have contributed to the understanding of resistance to targeted therapies in CLL are discussed. Strategies for managing resistance are reviewed, including translational, real-world, and clinical perspectives.


Assuntos
Leucemia Linfocítica Crônica de Células B , Tirosina Quinase da Agamaglobulinemia , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico
18.
Int J Infect Dis ; 105: 274-276, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33607304

RESUMO

Immune modulation in COVID-19 is emerging as an important therapeutic strategy as increasing evidence suggests that inflammatory pathways are implicated in lung damage. Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, are commonly used to treat indolent B-cell neoplasms and chronic graft-versus-host disease (GvHD). Given their potential to suppress pulmonary inflammatory cytokines and lessen acute lung injury, this could be applicable in the context of hospitalised COVID-19 patients. We describe an 81 year-old male receiving ibrutinib for Waldenstrom macroglobulinaemia (WM) who was hospitalised with COVID-19. On stopping the BTKi due to concerns of additional immunosuppression, he required non-invasive ventilation (NIV) in the intensive care unit (ICU) and demonstrated prompt clinical recovery when ibrutinib was reinstated. Continuing ibrutinib in patients with COVID-19 may be advantageous given its immunomodulatory properties and withdrawal of ibrutinib therapy may be detrimental. Further evidence is required to explore the potential therapeutic impact of BTKis and other immunomodulatory agents on the clinical course of COVID-19 as is currently being carried out in a number of clinical trials.


Assuntos
Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , COVID-19/tratamento farmacológico , COVID-19/imunologia , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adenina/uso terapêutico , Idoso de 80 Anos ou mais , Humanos , Imunomodulação , Masculino , SARS-CoV-2/imunologia , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/imunologia
19.
J Hematol Oncol ; 14(1): 15, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441177

RESUMO

Bruton's tyrosine kinase (BTK) inhibitors, drugs utilized in cancer, are being repurposed for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (COVID-19). Recently, BTK inhibitors acalabrutinib and ibrutinib have been found to protect against pulmonary injury in a small group of patients infected with SARS-CoV-2. The high levels of pro-inflammatory cytokines found in the circulation of COVID-19 patients with severe lung disease suggest the involvement of the innate immune system in this process. Understanding the potential mechanism of action of BTK inhibition in SARS-CoV-2 is clearly of importance to determine how acalabrutinib, ibrutinib and possibly other BTK inhibitors may provide protection against lung injury.


Assuntos
Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/uso terapêutico , COVID-19/tratamento farmacológico , Piperidinas/uso terapêutico , Pirazinas/uso terapêutico , SARS-CoV-2 , Adenina/uso terapêutico , COVID-19/metabolismo , Citocinas/genética , Citocinas/metabolismo , Reposicionamento de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos
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