Bruton’s Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures

Clinical development of BTK kinase inhibitors for treating autoimmune diseases has lagged behind development of these drugs for treating cancers, due in part from concerns over the lack of selectivity and associated toxicity profiles of first generation drug candidates when used in the long term treatment of immune mediated diseases. Second generation BTK inhibitors have made great strides in limiting off-target activities for distantly related kinases, though they have had variable success at limiting cross-reactivity within the more closely related TEC family of kinases. We investigated the BTK specificity and toxicity profiles, drug properties, disease associated signaling pathways, clinical indications, and trial successes and failures for the 13 BTK inhibitor drug candidates tested in phase 2 or higher clinical trials representing 7 autoimmune and 2 inflammatory immune-mediated diseases. We focused on rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE) where the majority of BTK nonclinical and clinical studies have been reported, with additional information for pemphigus vulgaris (PV), Sjogren’s disease (SJ), chronic spontaneous urticaria (CSU), graft versus host disease (GVHD), and asthma included where available. While improved BTK selectivity versus kinases outside the TEC family improved clinical toxicity profiles, less profile distinction was evident within the TEC family. Analysis of genetic associations of RA, MS, and SLE biomarkers with TEC family members revealed that BTK and TEC family members may not be drivers of disease. They are, however, mediators of signaling pathways associated with the pathophysiology of autoimmune diseases. BTK in particular may be associated with B cell and myeloid differentiation as well as autoantibody development implicated in immune mediated diseases. Successes in the clinic for treating RA, MS, PV, ITP, and GVHD, but not for SLE and SJ support the concept that BTK plays an important role in mediating pathogenic processes amenable to therapeutic intervention, depending on the disease. Based on the data collected in this study, we propose that current compound characteristics of BTK inhibitor drug candidates for the treatment of autoimmune diseases have achieved the selectivity, safety, and coverage requirements necessary to deliver therapeutic benefit.

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Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry ◽

10.2174/1871523011107020078 ◽

2011 ◽

Vol 10 (2) ◽

pp. 78-84 ◽

Cited By ~ 11

Author(s):

Charles J. Malemud

Keyword(s):

Rheumatoid Arthritis ◽

Rheumatic Disease ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Intracellular Signaling Pathways ◽

Immune Mediated

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Machine Learning for Predicting Risk of Drug-Induced Autoimmune Diseases by Structural Alerts and Daily Dose

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18137139 ◽

2021 ◽

Vol 18 (13) ◽

pp. 7139

Author(s):

Yue Wu ◽

Jieqiang Zhu ◽

Peter Fu ◽

Weida Tong ◽

Huixiao Hong ◽

...

Keyword(s):

Machine Learning ◽

Autoimmune Diseases ◽

Odds Ratio ◽

Area Under Curve ◽

Predictive Performance ◽

Drug Induced ◽

Drug Candidates ◽

Daily Dose ◽

Structural Alerts ◽

Underlying Mechanisms

An effective approach for assessing a drug’s potential to induce autoimmune diseases (ADs) is needed in drug development. Here, we aim to develop a workflow to examine the association between structural alerts and drugs-induced ADs to improve toxicological prescreening tools. Considering reactive metabolite (RM) formation as a well-documented mechanism for drug-induced ADs, we investigated whether the presence of certain RM-related structural alerts was predictive for the risk of drug-induced AD. We constructed a database containing 171 RM-related structural alerts, generated a dataset of 407 AD- and non-AD-associated drugs, and performed statistical analysis. The nitrogen-containing benzene substituent alerts were found to be significantly associated with the risk of drug-induced ADs (odds ratio = 2.95, p = 0.0036). Furthermore, we developed a machine-learning-based predictive model by using daily dose and nitrogen-containing benzene substituent alerts as the top inputs and achieved the predictive performance of area under curve (AUC) of 70%. Additionally, we confirmed the reactivity of the nitrogen-containing benzene substituent aniline and related metabolites using quantum chemistry analysis and explored the underlying mechanisms. These identified structural alerts could be helpful in identifying drug candidates that carry a potential risk of drug-induced ADs to improve their safety profiles.

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KOREA'S FIRST-GENERATION DIVIDED FAMILIES: The End of the Line?

World Affairs ◽

10.1177/00438200211024746 ◽

2021 ◽

pp. 004382002110247

Author(s):

James Alexander Foley

Keyword(s):

First Generation ◽

Korean War ◽

Family Members ◽

Red Cross ◽

Family Separation ◽

The Korean War ◽

History Of ◽

Successes And Failures

This article describes and analyzes the desperate situation of Korean first-generation divided family members who are still separated from their relatives nearly 70 years since the end of the Korean War (1950–1953). I aim to provide the reader with a reasonable quantification of the problem and make projections as to this first generation's likely future survival. The elements of the approach adopted to resolve the issue of family separation by the humanitarian bodies charged with addressing the problem, the Red Cross Societies of the two Koreas are described, and suggestions are made for improvement. The reunion program's successes and failures are critically assessed as is the key role played by the Red Cross Talks in the history of inter-Korean relations. Finally, conclusions are drawn as to the practical measures which may contribute to a resolution to the problem before the final disappearance of Korea's first generation of aged, separated family members.

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Identification of Potential Biomarkers and Pathways in Neonatal Hypoxic-Ischemic Brain Injury: Based on Bioinformatics Technology

10.21203/rs.3.rs-777916/v1 ◽

2021 ◽

Author(s):

Shangbin Li ◽

Shuangshuang Li ◽

Qian Zhao ◽

Jiayu Huang ◽

Jinfeng Meng ◽

...

Keyword(s):

Signaling Pathways ◽

Gene Expression Omnibus ◽

Biological Processes ◽

Ischemic Brain ◽

Protein Protein Interaction ◽

Immune Mediated ◽

Disability Rate ◽

Potential Biomarker ◽

Microarray Datasets ◽

Cerebral Cortex Tissue

Abstract Background Neonatal hypoxic-ischemic brain damage (HIBD) is one of the most common serious diseases in newborns, with a high mortality and disability rate. This study aims to use the bioinformatics analysis to identify potential hematologic/immune systems tissue-specific genes and related signaling pathways neonatal HIBD.Methods Microarray datasets in HIBD were downloaded from the Gene Expression Omnibus database, and DEGs were identified by R software.Enrichment analyses were performed and protein–protein interaction networks were constructed to understand the functions and enriched pathways of DEGs and to identify central genes and key modules. Results In the cerebral cortex tissue with HIBD, 2598 DEGs were identified, including 2362 up-regulated and 236 down-regulated DEGs. In the blood with HIBD, 1442 DEGs were identified, including 540 up-regulated and 902 down-regulated DEGs. The results of biological processes and KEGG enrichment were very similar in DEGs of the two kinds of tissues, and both involved inflammation, immunity and apoptosis. The common DEGs of the two kinds of tissues also showed similar results in biological processes and KEGG enrichment.and four hematologic/immune system tissues specifically expressed potential biomarker genes were confirmed through a variety of methods, which were verified by GEO datasets and published experimental research. Conclusion The DEGs of HIBD including the potential peripheral biomarkers TYROBP, ITGAM, EGR1 and HMOX1, which may play a role in the pathogenesis of HIBD through inflammation and immune-mediated signaling pathways.

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Hematopoietic Cell Transplantation for Benign Hematological Disorders and Solid Tumors

Hematology ◽

10.1182/asheducation-2003.1.372 ◽

2003 ◽

Vol 2003 (1) ◽

pp. 372-397 ◽

Cited By ~ 35

Author(s):

Rainer F. Storb ◽

Guido Lucarelli ◽

Peter A. McSweeney ◽

Richard W. Childs

Keyword(s):

Autoimmune Diseases ◽

Aplastic Anemia ◽

Solid Tumors ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Family Members ◽

Hematopoietic Cell ◽

Allogeneic Hct ◽

The Status ◽

Autologous Hct

Abstract Allogeneic hematopoietic cell transplantation (HCT) has been successfully used as replacement therapy for patients with aplastic anemia and hemoglobinopathies. Both autologous and allogeneic HCT following high-dose chemotherapy can correct manifestations of autoimmune diseases. The impressive allogeneic graft-versus-tumor effects seen in patients given HCT for hematological malignancies have stimulated trials of allogeneic immunotherapy in patients with otherwise refractory metastatic solid tumors. This session will update the status of HCT in the treatment of benign hematological diseases and solid tumors. In Section I, Dr. Rainer Storb reviews the development of nonmyeloablative conditioning for patients with severe aplastic anemia who have HLA-matched family members. He also describes the results in patients with aplastic anemia given HCT from unrelated donors after failure of responding to immunosuppressive therapy. The importance of leuko-poor and in vitro irradiated blood product transfusions for avoiding graft rejection will be discussed. In Section II, Dr. Guido Lucarelli reviews the status of marrow transplantation for thalassemia major and updates results obtained in children with class I and class II severity of thalassemia. He also describes results of new protocols for class III patients and efforts to extend HCT to thalassemic patients without HLA-matched family members. In Section III, Dr. Peter McSweeney reviews the current status of HCT for severe autoimmune diseases. He summarizes the results of autologous HCT for systemic sclerosis, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, and reviews the status of planned Phase III studies for autologous HCT for these diseases in North America and Europe. He also discusses a possible role of allogeneic HCT in the treatment of these diseases. In Section IV, Dr. Richard Childs discusses the development and application of nonmyeloablative HCT as allogeneic immunotherapy for treatment-refractory solid tumors. He reviews the results of pilot clinical trials demonstrating graft-versus-solid tumor effects in a variety of metastatic cancers and describes efforts to characterize the immune cell populations mediating these effects, as well as newer methods to target the donor immune system to the tumor.

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