Targeting B Cells and Microglia in Multiple Sclerosis With Bruton Tyrosine Kinase Inhibitors

JAMA Neurology, Journal Year: 2023, Volume and Issue: 80(4), P. 404 - 404

Published: Feb. 13, 2023

Importance Currently, disease-modifying therapies for multiple sclerosis (MS) use 4 mechanisms of action: immune modulation, suppressing cell proliferation, inhibiting migration, or cellular depletion. Over the last decades, repertoire substantially increased because conceptual progress that not only T cells but also B play an important pathogenic role in MS, fostered by empirical success cell–depleting antibodies against surface molecule CD20. Notwithstanding this advance, a continuous absence may harbor safety risks, such as decline endogenous production immunoglobulins. Accordingly, novel cell–directed MS are development, inhibitors targeting Bruton tyrosine kinase (BTK). Observations BTK is centrally involved receptor–mediated activation cells, one key requirement development autoreactive myeloid macrophages and microglia. Various compounds differ their binding mode, selectivity specificity, relative inhibitory concentration, potential to enter central nervous system. The latter be assessing whether inhibition promising strategy control inflammatory circuits within brain, process assumed drive progression. clinical trials using currently conducted patients with relapsing-remitting well progressive so far generating encouraging data regarding efficacy safety. Conclusions Relevance While approach highly promising, several questions remain unanswered, long-term effects treatment CNS disease. Potential changes circulating antibody levels should evaluated compared Also CNS, which depends on given compound. Remaining involve where fit landscape therapeutics. A comparative analysis distinct properties necessary identify used relapsing vs forms clarify agent most suitable sequential after anti-CD20 treatment.

Language: Английский

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Small molecule protein kinase inhibitors approved by regulatory agencies outside of the United States

Pharmacological Research, Journal Year: 2023, Volume and Issue: 194, P. 106847 - 106847

Published: July 15, 2023

Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in pathogenesis many autoimmune neoplastic disorders kinase antagonists have become an important drug target. Although efficacy imatinib treatment chronic myelogenous leukemia United States 2001 was main driver inhibitor discovery, this preceded by approval fasudil (a ROCK antagonist) Japan 1995 for cerebral vasospasm. There are 21 small molecule inhibitors that approved China, Japan, Europe, South Korea not Sates 75 FDA-approved States. Of agents, eleven target receptor protein-tyrosine kinases, eight inhibit nonreceptor two block protein-serine/threonine kinases. All drugs orally bioavailable or topically effective. non-FDA drugs, sixteen prescribed diseases, three directed toward inflammatory disorders, one is used glaucoma, management The leading targets both international regulatory agencies FDA members EGFR family, VEGFR JAK family. One-third internationally compliant with Lipinski's rule five drugs. relies on four parameters including molecular weight, number hydrogen bond donors acceptors, Log partition coefficient.

Language: Английский

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Small Molecule Targeting Immune Cells: A Novel Approach for Cancer Treatment

Biomedicines, Journal Year: 2023, Volume and Issue: 11(10), P. 2621 - 2621

Published: Sept. 24, 2023

Conventional and cancer immunotherapies encompass diverse strategies to address various types stages. However, combining these approaches often encounters limitations such as non-specific targeting, resistance development, high toxicity, leading suboptimal outcomes in many cancers. The tumor microenvironment (TME) is orchestrated by intricate interactions between immune non-immune cells dictating progression. An innovative avenue therapy involves leveraging small molecules influence a spectrum of resistant cell populations within the TME. Recent discoveries have unveiled phenotypically cohort innate-like T (ILT) hybrid (HCs) exhibiting novel characteristics, including augmented proliferation, migration, exhaustion, evasion immunosurveillance, reduced apoptosis, drug resistance, heightened metastasis frequency. Leveraging small-molecule immunomodulators target players presents an exciting frontier developing immunotherapies. Moreover, molecule modulators with immunotherapy can synergistically enhance inhibitory impact on progression empowering system meticulously fine-tune responses TME, bolstering its capacity recognize eliminate cells. This review outlines involving that modify potentially revolutionizing therapeutic interventions enhancing anti-tumor response.

Language: Английский

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A review of Bruton’s tyrosine kinase inhibitors in multiple sclerosis

Therapeutic Advances in Neurological Disorders, Journal Year: 2024, Volume and Issue: 17

Published: Jan. 1, 2024

Bruton’s tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed B-cells and myeloid cells, key progenitors which include dendritic microglia macrophages, integral effectors MS pathogenesis, along with mast establishing the relevance to diverse autoimmune conditions. First-generation currently utilized treatment B-cell malignancies show efficacy modulation. depleting therapies have shown success as disease-modifying treatments (DMTs) MS, highlighting potential for this indication; however, first-generation exhibit a challenging safety profile that unsuitable chronic use, required DMTs. A second generation highly selective has modulating MS-relevant mechanisms pathogenesis preclinical well clinical studies. Six these undergoing development three also under investigation spontaneous urticaria (CSU), rheumatoid arthritis (RA) systemic lupus erythematosus (SLE). Phase II trials selected showed reductions new gadolinium-enhancing lesions on magnetic resonance imaging scans; yet be ascertained use. Understanding developing by combining insights from ongoing phase III second-generation CSU, RA SLE. This narrative review investigates DMT, improved selectivity inhibitors, comparative established thus far through programmes proposed implications female reproductive health long-term administration.

Language: Английский

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Navigating the changing landscape of BTK-targeted therapies for B cell lymphomas and chronic lymphocytic leukaemia

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(12), P. 867 - 887

Published: Nov. 1, 2024

Language: Английский

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