scholarly journals Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective

2021 ◽  
Vol 22 (14) ◽  
pp. 7641
Author(s):  
Chiara Brullo ◽  
Carla Villa ◽  
Bruno Tasso ◽  
Eleonora Russo ◽  
Andrea Spallarossa
Keyword(s):  
Drug Delivery ◽  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Chronic Inflammation ◽  
Medicinal Chemistry ◽  
The Past ◽  
Hematological Cancers ◽  
Btk Inhibitor ◽  
Btk Inhibitors ◽  
Leukemias And Lymphomas

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.

scholarly journals Bruton Tyrosine Kinase Inhibition and Its Role as an Emerging Treatment in Pemphigus

2021 ◽  
Vol 8 ◽  
Author(s):  
Aikaterini Patsatsi ◽  
Dedee F. Murrell
Keyword(s):  
Tyrosine Kinase ◽  
Pemphigus Vulgaris ◽  
Lymphocytic Leukemia ◽  
Proof Of Concept ◽  
Phase 2 Trial ◽  
Mantle Cell ◽  
Bruton Tyrosine Kinase ◽  
Btk Inhibitor ◽  
New Treatment ◽  
Btk Inhibitors

Bruton Tyrosine Kinase (BTK) has a key role in multiple pathways involved in inflammation and autoimmunity. Therefore, BTK has become a new therapeutic target for a group of hematologic and autoimmune disorders. The pharmaceutical industry has invested in the clinical development of BTK inhibitors during the last decade. Ibrutinib, for example, which was the first BTK inhibitor to be used in clinical trials, has two approved indications, mantle cell lymphoma and chronic lymphocytic leukemia, and remains under evaluation for additional indications. Rillzabrutinib (PRN1008) is a new, highly potent and selective inhibitor of BTK. Early studies performed in canine pemphigus demonstrated effectiveness. A proof-of-concept, multicenter, phase 2 trial has recently showed the efficacy and safety of oral rilzabrutinib in pemphigus vulgaris. In this mini review, we present evidence regarding the mechanisms affected by BTK inhibition and the concept of BTK inhibition as an emerging new treatment in pemphigus.

Recent advancements on Benzimidazole: A versatile scaffold in medicinal chemistry

2021 ◽  
Vol 21 ◽  
Author(s):  
Zohor Mohammad Mahdi Alzhrani ◽  
Mohammad Mahboob Alam ◽  
Syed Nazreen
Keyword(s):  
Clinical Trials ◽  
Medicinal Chemistry ◽  
Biological Activities ◽  
Review Article ◽  
Present Review ◽  
Benzimidazole Derivatives ◽  
The Past ◽  
Anti Inflammatory

: Benzimidazole is nitrogen containing fused heterocycle which has been extensively explored in medicinal chemistry. Benzimidizole nucleus has been found to possess various biological activities such as anticancer, antimicrobial, anti-inflammatory, antiviral, antitubercular and antidiabetic. A number of benzimidazoles such as bendamustine, pantoprazole have been approved for the treatment of various illnesses whereas galeterone and GSK461364 are in clinical trials. The present review article gives an overview about the different biological activities exhibited by the benzimidazole derivatives as well as different methods used for the synthesis of benzimidazole derivatives for the past ten years.

scholarly journals Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances

Leukemia ◽  
2020 ◽  
Author(s):  
Tingyu Wen ◽  
Jinsong Wang ◽  
Yuankai Shi ◽  
Haili Qian ◽  
Peng Liu
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Drug Approval ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase ◽  
Btk Inhibitor ◽  
Btk Inhibitors ◽  
Potential Efficiency

Abstract Bruton’s tyrosine kinase (BTK) inhibitor is a promising novel agent that has potential efficiency in B-cell malignancies. It took approximately 20 years from target discovery to new drug approval. The first-in-class drug ibrutinib creates possibilities for an era of chemotherapy-free management of B-cell malignancies, and it is so popular that gross sales have rapidly grown to more than 230 billion dollars in just 6 years, with annual sales exceeding 80 billion dollars; it also became one of the five top-selling medicines in the world. Numerous clinical trials of BTK inhibitors in cancers were initiated in the last decade, and ~73 trials were intensively announced or updated with extended follow-up data in the most recent 3 years. In this review, we summarized the significant milestones in the preclinical discovery and clinical development of BTK inhibitors to better understand the clinical and commercial potential as well as the directions being taken. Furthermore, it also contributes impactful lessons regarding the discovery and development of other novel therapies.

Influence of Btk Inhibitors on Antitumor Activity of Natural Killer Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2742-2742
Author(s):  
Marta Siernicka ◽  
Kamil Bojarczuk ◽  
Malgorzata Bobrowicz ◽  
Michal Dwojak ◽  
Beata Pyrzynska ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Clinical Trials ◽  
Antitumor Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
Cytokine Secretion ◽  
Target Cells ◽  
Btk Inhibitor ◽  
Hodgkin's Lymphomas ◽  
Btk Inhibitors

Abstract Small molecule Bruton's tyrosine kinase (Btk) inhibitors are extensively studied in preclinical investigations and clinical trials in the treatment of hematological malignancies derived from B-cells. Ibrutinib, due to its safety and efficiency, has been recently approved for the treatment of patients with Chronic Lymphocytic Leukemia (CLL) who received at least one prior therapy. Moreover, another Btk inhibitor AVL-292 is currently tested in clinical trials in patients with B Cell Non-Hodgkin's Lymphomas, CLL and Waldenstrom Macroglobulinemia. Despite a huge therapeutic potential of Btk inhibitors we have recently demonstrated that both natural killer (NK) cells cytotoxicity and degranulation are significantly impaired upon ibrutinib treatment (Bojarczuk et al., Leukemia 2014). Since NK cells are effectors of innate immune system capable to kill tumor cells directly and in the mechanism of antibody dependent cell-mediated cytotoxicity (ADCC), which constitutes one of the major mechanism of monoclonal antibodies widely used in hematooncology, in our ongoing studies we are focused to determine in details the influence of various Btk inhibitors on NK cells cytotoxicity, degranulation, cytokine secretion and expression of activatory/inhibitory receptors. All experiments were performed fully in vitro using human primary NK cells isolated from PBMC of healthy donors as well as NK92 and NK92.CD16 cell lines. To determine cytolytic activity of NK cells CFSE/PI flow cytometry assay was used. Cytokine secretion and NK cells degranulation, evaluated as the expression of CD107a on the surface of NK cells, were determined with flow cytometry upon incubation with target cells for 4 h. Phenotype of NK cells pre-incubated with tested compounds was determined with flow cytometry using antibodies conjugated with fluorochromes. The initial results of our studies show that various Btk inhibitors differentially regulate NK cells antitumor activity. Ibrutinib and AVL-292 which covalently bind to cysteines at the position 481 significantly inhibit NK cells cytotoxicity. Interestingly, we have observed that pre-incubation of NK cells with ibrutinib as well as AVL-292 results in down-regulation of CD25 and CD69. This effect was not observed upon treatment of NK cells with CGI-1746, a reversible Btk inhibitor which blocks phosphorylation of BTK in Y551 and Y223. Expression of NK cells activatory receptors such as NKp30, NK44, NKp46, NKG2D, DNAM-1 and CD16 remained unchanged. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A Review on Fast Dissolving Tablet

2017 ◽  
Vol 8 (03) ◽  
Author(s):  
Sagar T. Malsane ◽  
Smita S. Aher ◽  
R. B. Saudagar
Keyword(s):  
Drug Delivery ◽  
Patient Compliance ◽  
Research Area ◽  
Oral Route ◽  
Dosage Forms ◽  
The Novel ◽  
The Past ◽  
Orally Disintegrating Tablets ◽  
Novel Drug ◽  
Experience Difficulty

Oral route is presently the gold standard in the pharmaceutical industry where it is regarded as the safest, most economical and most convenient method of drug delivery resulting in highest patient compliance. Over the past three decades, orally disintegrating tablets (FDTs) have gained considerable attention due to patient compliance. Usually, elderly people experience difficulty in swallowing the conventional dosage forms like tablets, capsules, solutions and suspensions because of tremors of extremities and dysphagia. In some cases such as motion sickness, sudden episodes of allergic attack or coughing, and an unavailability of water, swallowing conventional tablets may be difficult. One such problem can be solved in the novel drug delivery system by formulating “Fast dissolving tablets” (FDTs) which disintegrates or dissolves rapidly without water within few seconds in the mouth due to the action of superdisintegrant or maximizing pore structure in the formulation. The review describes the various formulation aspects, superdisintegrants employed and technologies developed for FDTs, along with various excipients, evaluation tests, marketed formulation and drugs used in this research area.

PD-L1 Inhibitors for the Treatment of Prostate Cancer

2020 ◽  
Vol 21 (15) ◽  
pp. 1558-1565
Author(s):  
Matteo Santoni ◽  
Francesco Massari ◽  
Liang Cheng ◽  
Alessia Cimadamore ◽  
Marina Scarpelli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
T Lymphocytes ◽  
Chronic Inflammation ◽  
Immune Cells ◽  
Response To Therapy ◽  
Complex Series

The carcinogenesis of prostate cancer (PCa) results from a complex series of events. Chronic inflammation and infections are crucial in this context. Infiltrating M2 type macrophages, as well as neutrophils and T lymphocytes, contribute to PCa development, progression and response to therapy. The preliminary findings on the efficacy of immunotherapy in patients with PCa were not encouraging. However, a series of studies investigating anti-PD-L1 agents such as Atezolizumab, Avelumab and Durvalumab used alone or in combination with other immunotherapies, chemotherapy or locoregional approaches are in course in this tumor. In this review, we illustrate the role of immune cells and PD-L1 expression during PCa carcinogenesis and progression, with a focus on ongoing clinical trials on anti-PD-L1 agents in this context.

Recent Nanocarrier Approaches for Targeted Drug Delivery in Cancer Therapy

2020 ◽  
Vol 13 ◽  
Author(s):  
Rohit Bhatia ◽  
Amit Sharma ◽  
Raj Kumar Narang ◽  
Ravindra K. Rawal
Keyword(s):  
Drug Delivery ◽  
Polymeric Micelles ◽  
Mesoporous Silica Nanoparticles ◽  
Treatment Strategies ◽  
Human Beings ◽  
The Past ◽  
Organ Systems ◽  
Metal Organic ◽  
Continuous Progress ◽  
Chemotherapeutic Treatment

: Cancer is one of the most serious health concerns in 21st century whose prevalence is beyond boundaries and can affect any organ of human beings. The conventional chemotherapeutic treatment strategies lack specificity to tumours and are associated with toxic effects on immune system and other organ systems. In the past decades, there has been a continuous progress in the development of smart nanocarrier systems for target specific delivery of drugs against variety of tumours including intracellular gene-specific targeting. These nanocarriers are able to recognize the tumour cells and deliver the therapeutic agent in fixed proportions causing no or very less harm to healthy cells. Nanosystems have modified physicochemical properties, improved bioavailability and long retention in blood which enhances their potency. A huge number of nanocarrier based formulations have been developed and are in clinical trials. Nanocarrier systems include polymeric micelles, liposomes, dendrimers, carbon nanotubes, gold nanoparticles, etc. Recent advancements in nanocarrier systems include mesoporous silica nanoparticles (MSNs), metal organic frame works and quantum dots. In the present review, various nanocarrier based drug delivery systems along with their applications in the management of cancer have been described with special emphasis on MSNs.

scholarly journals Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

2020 ◽  
Vol 12 ◽  
pp. 175883592092006
Author(s):  
Hang-Ping Yao ◽  
Sreedhar Reddy Suthe ◽  
Xiang-Min Tong ◽  
Ming-Hai Wang
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Targeted Therapeutics ◽  
Antibody Drug Conjugates ◽  
Drug Candidates ◽  
Drug Conjugates ◽  
Ron Receptor ◽  
Antibody Drug

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

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