Current therapeutic strategies and perspectives in refractory ITP: What have we learned recently?

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Авг. 8, 2022

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder featured by increased platelet destruction and deficient megakaryocyte maturation. First-line treatments include corticosteroids, intravenous immunoglobulin anti-D immunoglobulin. Second-line consist of rituximab, thrombopoietin receptor agonists splenectomy. Although most patients benefit from these treatments, individualized treatment approach warranted due to the large heterogeneity among ITP patients. In addition, may relapse there remains a subset who become refractory treatments. The management still challenge. This review aims summarize emerging therapeutic approaches for in several categories according their different targets, including macrophages, platelets/megakaryocytes, T cells, B endothelial cells. Moreover, current strategies combination regimens are also discussed.

Язык: Английский

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

JAMA Neurology, Год журнала: 2023, Номер 80(4), С. 404 - 404

Опубликована: Фев. 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.

Язык: Английский

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

Pharmacological Research, Год журнала: 2023, Номер 194, С. 106847 - 106847

Опубликована: Июль 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.

Язык: Английский

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Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib

PLoS ONE, Год журнала: 2023, Номер 18(8), С. e0290872 - e0290872

Опубликована: Авг. 31, 2023

Bruton's tyrosine kinase (BTK) is the target of therapeutic agent, Ibrutinib, that treats chronic lymphocyte leukemia (CLL), mantle cell lymphoma (MCL) and other B malignancies. Ibrutinib a first in class, covalent BTK inhibitor limits B-cell survival proliferation. Designing new inhibitors has been an important objective for advancing development improved agents against cancer autoimmune disorders. Based on success several second-generation irreversible have developed exhibit fewer off-target effects. However, binding-mode their interaction with Btk not experimentally determined evaluated at atomic resolution. Here we crystal structure domain complex acalabrutinib. In addition, report BTK/tirabrutinib compare these structures previously solved structures. The provide insight superior selectivity reported acalabrutinb guide future development.

Язык: Английский

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

Biomedicines, Год журнала: 2023, Номер 11(10), С. 2621 - 2621

Опубликована: Сен. 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.

Язык: Английский

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