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      Kinase inhibition in autoimmunity and inflammation

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          Abstract

          Despite recent advances in the treatment of autoimmune and inflammatory diseases, unmet medical needs in some areas still exist. One of the main therapeutic approaches to alleviate dysregulated inflammation has been to target the activity of kinases that regulate production of inflammatory mediators. Small-molecule kinase inhibitors have the potential for broad efficacy, convenience and tissue penetrance, and thus often offer important advantages over biologics. However, designing kinase inhibitors with target selectivity and minimal off-target effects can be challenging. Nevertheless, immense progress has been made in advancing kinase inhibitors with desirable drug-like properties into the clinic, including inhibitors of JAKs, IRAK4, RIPKs, BTK, SYK and TPL2. This Review will address the latest discoveries around kinase inhibitors with an emphasis on clinically validated autoimmunity and inflammatory pathways.

          Abstract

          Unmet medical needs in the treatment of autoimmune and inflammatory diseases still exist. This Review discusses the activity of kinases that regulate production of inflammatory mediators and the recent advances in developing inhibitors to target such kinases.

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          Most cited references264

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          Pattern recognition receptors and inflammation.

          Infection of cells by microorganisms activates the inflammatory response. The initial sensing of infection is mediated by innate pattern recognition receptors (PRRs), which include Toll-like receptors, RIG-I-like receptors, NOD-like receptors, and C-type lectin receptors. The intracellular signaling cascades triggered by these PRRs lead to transcriptional expression of inflammatory mediators that coordinate the elimination of pathogens and infected cells. However, aberrant activation of this system leads to immunodeficiency, septic shock, or induction of autoimmunity. In this Review, we discuss the role of PRRs, their signaling pathways, and how they control inflammatory responses. 2010 Elsevier Inc. All rights reserved.
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            Acute respiratory distress syndrome

            The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30–40% in most studies. Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-resourced settings and in paediatric patients. Treatment focuses on lung-protective ventilation; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.
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              Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

              Given the scale and rapid spread of the 2019 novel coronavirus (2019-nCoV) acute respiratory disease, there is an immediate need for medicines that can help before a vaccine can be produced. Results of rapid sequencing of 2019-nCoV, coupled with molecular modelling based on the genomes of related virus proteins, 1 have suggested a few compounds that are likely to be effective, including the anti-HIV lopinavir plus ritonavir combination. BenevolentAI's knowledge graph is a large repository of structured medical information, including numerous connections extracted from scientific literature by machine learning. 2 Together with customisations bespoke to 2019-nCoV, we used BenevolentAI to search for approved drugs that could help, focusing on those that might block the viral infection process. We identified baricitinib, which is predicted to reduce the ability of the virus to infect lung cells. Most viruses enter cells through receptor-mediated endocytosis. The receptor that 2019-nCoV uses to infect lung cells might be ACE2, a cell-surface protein on cells in the kidney, blood vessels, heart, and, importantly, lung AT2 alveolar epithelial cells (figure ). These AT2 cells are particularly prone to viral infection. 3 One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1). Disruption of AAK1 might, in turn, interrupt the passage of the virus into cells and also the intracellular assembly of virus particles. 4 Figure The BenevolentAI knowledge graph The BenevolentAI knowledge graph integrates biomedical data from structured and unstructured sources. It is queried by a fleet of algorithms to identify new relationships to suggest new ways of tackling disease. 2019-nCoV=2019 novel coronavirus. AAK1=AP-2 associated kinase 1. GAK=cyclin g-associated kinase. JAK1/2=janus kinase 1/2. Of 378 AAK1 inhibitors in the knowledge graph, 47 have been approved for medical use and six inhibited AAK1 with high affinity. These included a number of oncology drugs such as sunitinib and erlotinib, both of which have been shown to inhibit viral infection of cells through the inhibition of AAK1. 5 However, these compounds bring serious side-effects, and our data infer high doses to inhibit AAK1 effectively. We do not consider these drugs would be a safe therapy for a population of sick and infected people. By contrast, one of the six high-affinity AAK1-binding drugs was the janus kinase inhibitor baricitinib, which also binds the cyclin G-associated kinase, another regulator of endocytosis. Because the plasma concentration of baricitinib on therapeutic dosing (either as 2 mg or 4 mg once daily) is sufficient to inhibit AAK1, we suggest it could be trialled, using an appropriate patient population with 2019-nCoV acute respiratory disease, to reduce both the viral entry and the inflammation in patients, using endpoints such as the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. 7
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                Author and article information

                Contributors
                ali@trex.bio
                Journal
                Nat Rev Drug Discov
                Nat Rev Drug Discov
                Nature Reviews. Drug Discovery
                Nature Publishing Group UK (London )
                1474-1776
                1474-1784
                19 October 2020
                : 1-25
                Affiliations
                [1 ]Discovery Department, TRex Bio, South San Francisco, CA USA
                [2 ]ISNI 0000 0004 0534 4718, GRID grid.418158.1, Early Discovery Biochemistry Department, , Genentech, ; South San Francisco, CA USA
                [3 ]Protein Science Group, Synthekine, Menlo Park, CA USA
                Author information
                http://orcid.org/0000-0002-9743-8716
                http://orcid.org/0000-0001-5377-2387
                Article
                82
                10.1038/s41573-020-0082-8
                7569567
                33077936
                263f00c2-ea56-49f0-b206-ff3e9c314a24
                © Springer Nature Limited 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 15 August 2020
                Categories
                Review Article

                drug discovery,immunology
                drug discovery, immunology

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