Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up.

Related collections

Most cited references 118

Record: found
Abstract: found
Article: not found

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

Peter Richardson, Ivan Griffin, Catherine Tucker … (2020)

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

0 comments Cited 725 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects

Shubhasree Banerjee, Ann Biehl, Massimo Gadina … (2017)

The Janus kinase/signal transduction and activator of transcription (JAK–STAT) signaling pathway is implicated in the pathogenesis of inflammatory and autoimmune diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases use JAKs and STATs to transduce intracellular signals. Mutations in JAK and STAT genes cause a number of immunodeficiency syndromes, and polymorphisms in these genes are associated with autoimmune diseases. The success of small-molecule JAK inhibitors (Jakinibs) in the treatment of rheumatologic disease demonstrates that intracellular signaling pathways can be targeted therapeutically to treat autoimmunity. Tofacitinib, the first rheumatologic Jakinib, is US Food and Drug Administration (FDA) approved for rheumatoid arthritis and is currently under investigation for other autoimmune diseases. Many other Jakinibs are in preclinical development or in various phases of clinical trials. This review describes the JAK–STAT pathway, outlines its role in autoimmunity, and explains the rationale/pre-clinical evidence for targeting JAK–STAT signaling. The safety and clinical efficacy of the Jakinibs are reviewed, starting with the FDA-approved Jakinib tofacitinib, and continuing on to next-generation Jakinibs. Recent and ongoing studies are emphasized, with a focus on emerging indications for JAK inhibition and novel mechanisms of JAK–STAT signaling blockade.

0 comments Cited 440 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis.

Srdan Verstovsek, Hagop Kantarjian, Ruben Mesa … (2010)

Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. We conducted a phase 1−2 trial of INCB018424 in patients with JAK2 V617F−positive or JAK2 V617F−negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)

0 comments Cited 330 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Athina Geronikaki: Role: Academic Editor

Journal

Journal ID (nlm-ta): Molecules

Journal ID (iso-abbrev): Molecules

Journal ID (publisher-id): molecules

Title: Molecules

Publisher: MDPI

ISSN (Electronic): 1420-3049

Publication date (Electronic): 22 July 2020

Publication date Collection: August 2020

Volume: 25

Issue: 15

Electronic Location Identifier: 3321

Affiliations

[1 ]Dipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, Viale Europa, 88100 Catanzaro, Italy; a.coricello@ 123456unicz.it (A.C.); francesco.mesiti@ 123456studenti.unicz.it (F.M.); maruca@ 123456unicz.it (A.M.)

[2 ]Net4Science srl, Campus Universitario ‘S. Venuta’, Università ‘Magna Græcia’ di Catanzaro, Viale Europa, 88100 Catanzaro, Italy; antonio.lupia@ 123456net4science.com

Author notes

[* ]Correspondence: alcaro@ 123456unicz.it ; Tel.: +39-0961-369-4197

Author information

Adriana Coricello https://orcid.org/0000-0002-3306-9261

Francesco Mesiti https://orcid.org/0000-0002-9968-4996

Antonio Lupia https://orcid.org/0000-0003-0870-2376

Annalisa Maruca https://orcid.org/0000-0002-6537-552X

Article

Publisher ID: molecules-25-03321

DOI: 10.3390/molecules25153321

PMC ID: 7435994

PubMed ID: 32707925

SO-VID: 8de0a7de-a21c-4e91-8c4b-4f2d3c3ae6f5

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 18 June 2020

Date accepted : 20 July 2020

Comments

Comment on this article

scite_

Smart Citations

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

Read this article at

Abstract

Related collections

Drug Repurposing Research Collection

Most cited references 118

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects

Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis.

Author and article information

Contributors

Journal

Affiliations

Author notes

Author information

Article

History

Categories

Comments

Comment on this article

Similar content 90

Cited by 16

Most referenced authors 2,085