pci-32765 and Neoplasms

Bruton's tyrosine kinase (BTK) regulates multiple important signaling pathways and plays a key role in the proliferation, survival, and differentiation of B-lineage cells and myeloid cells. BTK is a promising target for the treatment of hematologic malignancies. Ibrutinib, the first-generation BTK inhibitor, was approved to treat several B-cell malignancies. Despite the remarkable potency and efficacy of ibrutinib against various lymphomas and leukemias in the clinics, there are also some clinical limitations, such as off-target toxicities and primary/acquired drug resistance. As strategies to overcome these challenges, second- and third-generation BTK inhibitors, BTK-PROTACs, as well as combination therapies have been explored. In this review, we summarize clinical developments of the first-, second- and third-generation BTK inhibitors, as well as recent advances in BTK-PROTACs and ibrutinib-based combination therapies.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; B-Lymphocytes; Cyclin-Dependent Kinase 4; Drug Resistance, Neoplasm; Drug Therapy, Combination; Humans; Immunotherapy; Neoplasms; Piperidines; Protein Kinase Inhibitors

Bruton's tyrosine kinase (BTK) is a promising target in the treatment of various cancers. Despite the early success of BTK inhibitors in the clinic, these single-target drug therapies have limitations in their clinical applications, such as drug resistance. Several alternative strategies have been developed, including the use of dual inhibitors, to maximize the therapeutic potential of anticancer drugs. In this review, we highlight the scientific background and theoretical basis for developing BTK-based dual inhibitors, as well as the status of these agents in preclinical and clinical studies, and discuss further options in this field. We posit that these advances in BTK-based dual inhibitors confirm their feasibility for the treatment of refractory tumors, including those with drug resistance, and provide a framework for future drug design in this field. Accordingly, we anticipate increasingly rapid progress in the development of novel potent dual inhibitors and advanced clinical research on BTK-based dual inhibitors.

Topics: Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Drug Design; Humans; Neoplasms; Protein Kinase Inhibitors

Considerable progress has been made in the development of anticancer agents over the past few decades, and a lot of new anticancer agents from natural and synthetic sources have been produced. Among heterocyclic compounds, pyrimidine-fused bicyclic heterocycles possess a variety of biological activities such as anticancer, antiviral, etc. To date, 147 pyrimidine-fused bicyclic heterocycles have been approved for clinical assessment or are currently being used in clinic, 57 of which have been approved by FDA for clinical treatment of various diseases, and 22 of them are being used in the clinic for the treatment of different cancers. As the potentially privileged scaffolds, pyrimidine-fused bicyclic heterocycles may be used to discover new drugs with similar biological targets and improved therapeutic efficacy. This review aims to provide an overview of the anticancer applications and synthetic routes of 22 approved pyrimidine-fused bicyclic heterocyclic drugs in clinic.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Molecular Structure; Neoplasms; Pyrimidines; United States; United States Food and Drug Administration

The outbreak of the novel coronavirus disease 2019 (COVID-19) has emerged as one of the biggest global health threats worldwide. As of October 2020, more than 44 million confirmed cases and more than 1,160,000 deaths have been reported globally, and the toll is likely to be much higher before the pandemic is over. There are currently little therapeutic options available and new potential targets are intensively investigated. Recently, Bruton tyrosine kinase (BTK) has emerged as an interesting candidate. Elevated levels of BTK activity have been reported in blood monocytes from patients with severe COVID-19, compared with those from healthy volunteers. Importantly, various studies confirmed empirically that administration of BTK inhibitors (acalabrutinib and ibrutinib) decreased the duration of mechanical ventilation and mortality rate for hospitalized patients with severe COVID-19. Herein, we review the current information regarding the role of BTK in severe acute respiratory syndrome coronavirus 2 infections and the suitability of its inhibitors as drugs to treat COVID-19. The use of BTK inhibitors in the management of COVID-19 shows promise in reducing the severity of the immune response to the infection and thus mortality. However, BTK inhibition may be contributing in other ways to inhibit the effects of the virus and this will need to be carefully studied.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antiviral Agents; Benzamides; COVID-19; COVID-19 Drug Treatment; Humans; Lung; Molecular Targeted Therapy; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazines; Thrombosis

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Chemistry, Pharmaceutical; COVID-19 Drug Treatment; Drug Delivery Systems; Hematologic Neoplasms; Humans; Inflammation; Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; SARS-CoV-2

Cancer remains the most serious disease that threatens human health. Molecularly targeted cancer therapies, specifically small-molecule protein kinase inhibitors, form an important part of cancer therapy. Targeted covalent modification represents a proven approach to drug discovery with the recent FDA approvals of afatanib, ibrutinib, and osimertinib agents, which were designed to undergo an irreversible hetero-Michael addition reaction with a unique cysteine residue of a specific protein. Covalent inhibitors possess numerous advantages, including increased biochemical efficacy, longer duration of action, the high potential for improved therapeutic index due to lower effective dose, and the potential to inhibit certain drug resistance mechanisms. In this regard, the novel targeted anticancer agents whose activity is presumably dependent upon a hetero-Michael addition reaction with thiols are summarized in this article.

Topics: Animals; Antineoplastic Agents; Drug Design; Humans; Models, Molecular; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors

Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase that belongs to the TEC-family tyrosine kinases together with bone marrow-expressed kinase (BMX), redundant-resting lymphocyte kinase (RLK), and IL-2 inducible T-Cell kinase (ITK). All these proteins play a key role in the intracellular signaling of both B and T lymphocytes. Recently, some preclinical data have demonstrated that BTK is present in certain tumor subtypes and in other relevant cells that are contributing to the tumor microenvironment such as dendritic cells, macrophages, myeloid derived suppressor cells and endothelial cells. Ibrutinib (PCI-32765) is an orally available small molecule that acts as an inhibitor of the BTK and is approved for the treatment of patients with some hematological malignancies. It has been suggested that ibrutinib may also have a potential antitumor activity in solid neoplasms. In this sense, ibrutinib has the ability to revert polarization of TCD4+ to Th1 lymphocytes to increase the cytotoxic ability of T CD8+ and to regulate tumor-induced immune tolerance by acting over tumor infiltrating cells activity and immunosuppressive cytokines release. Furthermore, based on its molecular activity and safety, ibrutinib has been considered as a partner for treatment combination with PI3K/AKT/mTOR inhibitors or with immune-checkpoint inhibitors, inhibiting immunosuppressive signals from the tumor microenvironment, and overcoming the immune resistance to current anti-PD1/PDL1 immunotherapeutic drugs by the CXCR4/CXCL2 pathway regulation. Currently, a broad range of different studies are evaluating the activity of ibrutinib either as single agent or in combination in patients with solid tumors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Humans; Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction

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. In addition to inhibitory effects, recent studies have shown that ibrutinib has multiple immunomodulatory effects. It binds covalently to IL-2 inducible tyrosine kinase (Itk) in T lymphocytes and suppresses the survival of T-helper (Th) 2 cells. This changes the balance of Th1/Th2 cells toward Th1 subset, which are the main immune cells targeting tumor cells. The dual activity of ibrutinib has paid a great attention and several studies are evaluating the anti-tumor and immunomodulatory effects in cancer, autoimmune disorders and infectious diseases. In this article we review the inhibitory and immunomodulatory effects of ibrutinib in B-cell malignancies, autoimmune diseases and infections, as well as the communication between the Ror1 receptor tyrosine kinase and BCR and effects of ibrutinib on this crosstalk.

Topics: Adenine; Animals; Autoimmune Diseases; Humans; Immunologic Factors; Neoplasms; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Bruton's TK (BTK) is a promising biological target for therapeutic intervention of several diseases including inflammatory diseases and cancer/B cell malignancies. Numerous research groups are actively engaged in investigating the functions of BTK, and discovering potent and selective BTK inhibitors as drug candidates. Revealed by x-ray crystal structures with ligands of diverse chemical structures, the ability of BTK kinase domain to adopt various inactive conformations offers unique opportunities to identify highly potent and exquisitely selective inhibitors. Both reversible and covalent inhibitor approaches have yielded candidates demonstrating safety profiles and efficacies in multiple preclinical models of autoimmunity and oncology. Two BTK inhibitors have entered human clinical trials for oncology indications. Ibrutinib won the US FDA approval in November 2013 to become the first-in-class BTK inhibitor for treating mantle cell lymphoma. This encouraging outcome and the other on-going human studies could ultimately expand the utility of BTK inhibitors to broader autoimmune disease areas.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Autoimmune Diseases; Clinical Trials as Topic; Crystallography, X-Ray; Drug Discovery; Humans; Models, Molecular; Neoplasms; Piperidines; Protein Conformation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Small Molecule Libraries

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. Ongoing studies are evaluating ibrutinib in other types of non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma and Waldenström's macrogobulinemia, in larger Phase III studies in CLL and MCL, and in combination studies with monoclonal antibodies and chemotherapy. Future studies will combine ibrutinib with other promising novel agents currently in development in hematologic malignancies.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Combined Modality Therapy; Drug Evaluation, Preclinical; Humans; Neoplasms; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Treatment Outcome

Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors.. This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab.. The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%).. The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; B7-H1 Antigen; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neoplasms; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

This open-label, single-dose study was designed to characterize pharmacokinetics and safety profile of ibrutinib in hepatically impaired subjects. Each subject received single oral dose of ibrutinib (140 mg) following an overnight fast (hepatic impairment-mild [n = 6], moderate [n = 10], and severe [n = 8]; healthy control [n = 6]). Subjects with hepatic impairment showed significant increase in ibrutinib plasma exposures and fraction unbound ibrutinib. Compared to control group, mean exposure (AUC

Topics: Adenine; Adult; Aged; Area Under Curve; Biomarkers; Drug Monitoring; Female; Humans; Incidence; Liver Diseases; Liver Function Tests; Male; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Severity of Illness Index

Nowadays, PI3Kδ-γ dual inhibitors have been approved for the treatment of B-cell malignancies. Dual inhibition of PI3Kδ and PI3Kγ represents a unique therapeutic opportunity and may confer greater benefits than either isoform inhibition alone in the management of hematological malignancies. However, currently available dual inhibitors of PI3Kδ-γ compromise in at least one of several essential properties in terms of potency, selectivity, and pharmacokinetic (PK) profiles. Hence, the main challenge of our optimization campaign was to identify an oral available PI3Kδ-γ dual inhibitor with an optimum balance of potency, selectivity, and PK profiles. The medicinal chemistry efforts culminated in the discovery of compound

Topics: Animals; B-Lymphocytes; Class I Phosphatidylinositol 3-Kinases; Humans; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Rats

In this study, we report a case of a 77-year-old woman who was presented with anemia in the winter of 2002. She was diagnosed with cold agglutinin disease (CAD) and treated with corticosteroids. Further, her hemoglobin levels were maintained between 7.0 g/dl and 8.0 g/dl. In May 2019, mature peripheral blood lymphocytes increased with exacerbation of hemolytic anemia. The lymphocytes were positive for CD19 and CD20, but negative for CD5, CD10, and CD23. Additionally, they were positive for cell surface IgM-κ. The B-cell neoplasm could not be further subclassified due to the lack of BCL2-IgH and BCL1-IgH rearrangement and morphology. The IgM-κ-type M-protein was found in serum, and the direct Coombs test was negative for IgG but positive for C3b/C3d. These findings suggested that small B-cell neoplasm-associated M-protein was involved in the development of CAD through complement activation. Based on the presence of TP53 deletion, the patient was treated with ibrutinib monotherapy. Although hemolysis rapidly improved with a dramatic decrease in lymphocytes, she died from a cerebral hemorrhage. It is assumed that ibrutinib improved CAD through suppression of small B-cell neoplasm-related M-protein. CAD can precede lymphoproliferative disorders; however, the risk of ibrutinib-associated hemorrhage should be noted.

Topics: Adenine; Aged; Anemia, Hemolytic, Autoimmune; Female; Humans; Lymphoproliferative Disorders; Neoplasms; Piperidines

Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.

Topics: Adenine; Animals; Autophagy; Beclin-1; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; Enzyme Activation; Mice; Neoplasms; Nuclear Proteins; Phosphoprotein Phosphatases; Phosphorylation; Phosphotyrosine; Piperidines; Protein Binding; Proto-Oncogene Proteins c-akt; Signal Transduction; src-Family Kinases; Tacrolimus Binding Proteins

Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for patients with CD19 B-cell malignancies. Combination strategies that improve CAR T-cell potency, limit tumor environment-mediated immune dysfunction, and directly reduce tumor burden may increase the potential for durable clinical benefit of CAR T-cell therapy. Lisocabtagene maraleucel (liso-cel) is a product therapy candidate being tested in patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia. This study assessed the in vitro and in vivo functionality of CAR T cells transduced to express the anti-CD19 CAR of liso-cel in combination with ibrutinib or acalabrutinib. In prolonged stimulation assays, the presence of ibrutinib or acalabrutinib improved the CAR T-cell effector function. RNA-Seq analysis and surface marker profiling of these CAR T cells treated with ibrutinib but not acalabrutinib revealed gene expression changes consistent with skewing toward a memory-like, type 1 T-helper, Bruton tyrosine kinase phenotype. Ibrutinib or acalabrutinib improved CD19 tumor clearance and prolonged survival of tumor-bearing mice when used in combination with CAR T cells. A combination of the defined cell product therapy candidate, liso-cel, with ibrutinib or acalabrutinib is an attractive approach that may potentiate the promising clinical responses already achieved in CD19 B-cell malignancies with each of these single agents.

Topics: Adenine; Animals; Antigens, CD19; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers; Combined Modality Therapy; Cytokines; Cytotoxicity, Immunologic; Disease Models, Animal; Humans; Immunotherapy, Adoptive; Lymphocyte Activation; Mice; Neoplasms; Piperidines; Pyrazines; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome; Xenograft Model Antitumor Assays

Topics: Adenine; B-Lymphocytes; Cell Line; Humans; Mutation; Neoplasms; Piperidines; Protein Kinase Inhibitors

Topics: Adenine; B-Lymphocytes; Consensus; Humans; Immunosuppressive Agents; Mycoses; Neoplasms; Piperidines

Ibrutinib treatment has been shown to increase survival in patients with B cell malignancies. Real-life data suggest a large part of discontinuations are due to toxicities, impairing ibrutinib efficacy. We aimed to assess the impact of a pharmaceutical care program on the efficacy and safety of ibrutinib. This single-center, cohort, observational study enrolled patients with B cell malignancies. Patients were either assigned to the program or to receive usual care, based on physician decision. The program was conducted by clinical pharmacists specializing in oncology and included patient education for management of toxicities, adherence monitoring, interventions to reduce drug-drug interactions, and follow-up of transition from hospital to community. Between February 2014 and May 2017, we enrolled 155 patients, including 42 (27%) who were allocated to the program group and 113 (73%) to the usual care group. The effect of the program was beneficial in terms of time to treatment failure (p = 0.0005). The 30-month progression-free and overall survivals were significantly superior in the program group (respectively p = 0.002 and p = 0.004). Grade 3 or higher adverse events occurred more frequently for patients in the usual care group (15%) than program group (8%). A pharmaceutical care program provides a personalized environment for outpatient monitoring and control of the key risks associated with oral anticancer agents. This study shows evidence that management of ibrutinib treatment by clinical pharmacists results in significant improvement in survival and better tolerance than usual care.

Topics: Adenine; Aged; Aged, 80 and over; Cohort Studies; Efficiency, Organizational; Female; Humans; Male; Middle Aged; Neoplasms; Pharmaceutical Services; Pharmacists; Piperidines; Pyrazoles; Pyrimidines; Quality Improvement; Survival Analysis; Time Factors; Time-to-Treatment; Treatment Failure

Ibrutinib is a Burton tyrosine kinase inhibitor (BTKi) approved for the treatment of several hematologic malignancies. Analyze skin adverse events (SAE). All the patients treated with Ibrutinib featuring cutaneous adverse events were selected. Twenty five patients were retrieved with a median interval between Ibrutinib start and SAE time of onset of 120 days. Most common SAE observed involved hairs and nails. Eczematous reaction and leucocytoclastic vasculitis were also detected. One patient had a long-history Ibrutinib treatment and experienced numerous cutaneous adverse events. Infective disease such as superficial mycosis and impetigo were rarely present in our series. Despite the development of cutaneous SAE, all the patients continued their concomitant drugs without the onset of any further SAE. Our data suggest Ibrutinib-associated rash should be distinguished in early and late events and a careful dermatologic management of patients should be scheduled.

Topics: Adenine; Humans; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Topics: Adenine; B-Lymphocytes; Granuloma, Pyogenic; Humans; Neoplasms; Piperidines; Pyrazoles

Topics: Adenine; Atrial Fibrillation; Humans; Neoplasms; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Aged; Atrial Fibrillation; Comorbidity; Electrocardiography; Female; Heart Failure; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Patient Outcome Assessment; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies; Risk Factors

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Humans; Neoplasms; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Adult; Aged; Aged, 80 and over; B-Lymphocytes; Female; Humans; Incidence; Male; Middle Aged; Neoplasms; Opportunistic Infections; Piperidines; Pyrazoles; Pyrimidines; Young Adult

Ibrutinib (IBR), an irreversible Bruton's tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)-stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted immunotherapy. Amphiphilic egg phosphatidylglycerol (EPG) structure and strong IBR-EPG interactions render these nanocomplexes high IBR loading capacity, prolonged blood circulation, and optimal particle sizes (∼30 nm), which can effectively deliver IBR to the tumor, followed by subsequent internalization of IBR by TAMs through SA-mediated active targeting. In vitro and in vivo tests showed that the prepared SA/IBR/EPG nanocomplexes could preferentially accumulate in TAMs and exert potent antitumor activity. Immunofluorescence staining analysis further confirmed that SA/IBR/EPG remarkably inhibited angiogenesis and tumorigenic cytokines released by TAM and eventually suppressed tumor progression, without eliciting any unwanted effect. Thus, SA-decorated IBR nanocomplexes present a promising strategy for cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Ibrutinib (IBR), an irreversible Bruton's tyrosine kinase (BTK) inhibitor, is expected to be a potent therapeutic modality, given that BTK is overexpressed in tumor-associated macrophages (TAMs) and participates in promoting tumor progression, angiogenesis, and immunosuppression. However, rapid clearance in vivo and low tumor accumulation have rendered effective uptake of IBR by TAMs challenge. Herein, we designed and synthesized a sialic acid (SA)-stearic acid conjugate modified on the surface of nanocomplexes to encapsulate IBR (SA/IBR/EPG) for targeted delivery of IBR to TAMs. The developed SA/IBR/EPG nanocomplexes exhibited high efficiency in targeting TAMs and inhibiting BTK activation, consequently inhibiting Th2 tumorigenic cytokine release, reducing angiogenesis, and suppressing tumor growth. These results implied that the SA/IBR/EPG nanocomplex could be a promising strategy for TAM-targeting immunotherapy with minimal systemic side effects.

Topics: Adenine; Animals; Drug Delivery Systems; Immunotherapy; Macrophages; Male; Mice; N-Acetylneuraminic Acid; Nanoparticles; Neoplasms; Phosphatidylglycerols; Piperidines; Proton Magnetic Resonance Spectroscopy; Pyrazoles; Pyrimidines; Rats, Wistar; RAW 264.7 Cells; Stearic Acids

Topics: Abiraterone Acetate; Adenine; Antineoplastic Agents; Clinical Protocols; Dasatinib; Drug Costs; France; gamma-Glutamyl Hydrolase; Humans; Insurance, Pharmaceutical Services; Medical Oncology; Neoplasms; Nivolumab; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Recombinant Proteins; United States; Zoledronic Acid

Topics: Adenine; Aged; B-Lymphocytes; Hemorrhage; Humans; Neoplasms; Piperidines; Pyrazoles; Pyrimidines

Alterations in ERBB family members have been associated with many tumor malignancies. EGFR and ERBB2 have been extensively explored in clinical oncology and several drugs currently target them therapeutically. However, the significance of ERBB4 as a potential therapeutic target remains mostly unexplored, even though ERBB4 is overexpressed or mutated in many solid tumors. Using a unique functional protein microarray platform, we found that ibrutinib inhibits ERBB4 activity in the same nM range as its canonical target, BTK. Cell-based assays revealed that ibrutinib treatment inhibited cell growth and decreased phosphorylation of ERBB4 and downstream targets MEK and ERK in cancer cell lines with high levels of endogenous ERBB4. In vivo, ibrutinib-responsive mouse xenograft tumors showed decreased tumor volumes with ibrutinib treatment. Interestingly, global gene expression comparisons between responsive and non-responsive cells identified a signature featuring the WNT pathway that predicts growth responsiveness to ibrutinib. Non-responsive ERBB4-expressing cell lines featured elevated activity of the WNT pathway, through the overexpression of WNT5A. Moreover, inhibition of WNT5A expression led to an ibrutinib response in non-responsive cell lines. Our data show that inhibiting ERBB4 reduces cell growth in cells that have low WNT5A expression and reveal a link between the ERBB4 and WNT pathways.

Topics: A549 Cells; Adenine; Animals; Cell Proliferation; Cells, Cultured; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasms; Piperidines; Pyrazoles; Pyrimidines; Receptor, ErbB-4; Signal Transduction; Tumor Burden; Wnt-5a Protein; Xenograft Model Antitumor Assays

Paclitaxel is one of the most widely used antineoplastic drugs in the clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP-binding cassette subfamily B member 1 (ABCB1/P-glycoprotein) and subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here, we demonstrated that the Bruton tyrosine kinase inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and ABCC10 in cells overexpressing these transporters. Furthermore, we demonstrated that the ABCB1 or ABCC10 protein expression was not altered after treatment with ibrutinib for up to 72 hours using Western blot analysis. However, the ATPase activity of ABCB1 was significantly stimulated by treatment with ibrutinib. Molecular docking analysis suggested the binding conformation of ibrutinib within the large cavity of the transmembrane region of ABCB1. Importantly, ibrutinib could effectively enhance paclitaxel-induced inhibition on the growth of ABCB1- and ABCC10-overexpressing tumors in nude athymic mice. These results demonstrate that the combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance that could be of great clinical interest.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression; Humans; Male; Mice; Models, Molecular; Molecular Conformation; Multidrug Resistance-Associated Proteins; Neoplasms; Paclitaxel; Piperidines; Protein Binding; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Adenine; Antineoplastic Agents; Drug Evaluation; Humans; Neoplasms; Patient Selection; Piperazines; Piperidines; Pragmatic Clinical Trials as Topic; Pyrazoles; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Research Design

Adnectins are a family of binding proteins derived from the 10th type III domain of human fibronectin (10Fn3), which is part of the immunoglobulin superfamily and normally binds integrin. The 10Fn3 has the potential for broad therapeutic applications given its structural stability, ability to be manipulated, and its abundance in the human body. The most commonly studied adnectin is CT-322, which is an inhibitor of vascular endothelial growth factor receptor-2. A bispecific adnectin, El-Tandem, has also been developed and binds to epidermal growth factor receptor and insulin-like growth factor-1 receptor simultaneously. Pre-clinical studies have shown promising results in relation to reducing tumor growth, decreasing microvessel density, and promoting normalization of tumor architecture. The phase I trial with CT-322 demonstrates relatively low toxicities. However, the phase II study done with CT-322 in recurrent glioblastoma does not reveal as promising results.

Topics: Adenine; Angiogenesis Inhibitors; Antineoplastic Agents; Bortezomib; Clinical Trials as Topic; Drug Evaluation, Preclinical; Fibronectins; Humans; Lenalidomide; Molecular Targeted Therapy; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pyrazoles; Pyrimidines; Thalidomide; Vascular Endothelial Growth Factor Receptor-2

Topics: Adenine; Aniline Compounds; Antineoplastic Agents; Bevacizumab; Brentuximab Vedotin; Cost-Benefit Analysis; Drug Industry; Humans; Immunoconjugates; Neoplasms; Nitriles; Piperidines; Pyrazoles; Pyrimidines; Quinolines; State Medicine; Trastuzumab; United Kingdom