Tec family kinases are the second largest family of non-receptor tyrosine kinases, of critical importance to the biology of cells derived from the bone marrow. Significant progress in this area during the last decade revealed a role for several of these kinases in inflammatory and oncologic disorders. This led to the discovery and development of molecular targeted therapies against Tec kinases, most notably to date Btk, already showing promising clinical activity in B cell lymphoma and autoimmunity. As Btk does not carry oncogenic modifications, this also establishes a novel therapeutic paradigm, based on targeting ancillary pathways recruited by the pathogenic process to become pivotal to cancer cell's biology. This issue focuses on biology and translation of Tec kinases, at the cross-roads between immunology and cancer.
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| http://dx.doi.org/10.3109/08830185.2012.671692 | DOI Listing |
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Efficacy and safety of ritlecitinib in Asian patients with alopecia areata: A subgroup analysis of the ALLEGRO phase 2b/3 trial.
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Pfizer Japan Inc, Tokyo, Japan.
This subgroup analysis of the ALLEGRO phase 2b/3 study (NCT3732807) assessed the efficacy and safety of multiple doses of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, in Asian patients with alopecia areata (AA). Patients aged ≥12 years with AA and ≥50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (with or without 4-week 200-mg loading dose ["200/50" or "200/30"]) or 10 mg or placebo for 24 weeks, followed by a 24-week extension, in which patients initially assigned to placebo switched to 200/50 or 50 mg. In this subgroup analysis, Asian patients with response based on achieving a Severity of Alopecia Tool (SALT) score ≤20, SALT ≤10, ≥2-grade improvement or normal score on the eyebrow assessment (EBA) scale, and ≥2-grade improvement or normal score on the eyelash assessment (ELA) scale were evaluated through week 48.
View Article and Find Full Text PDFHeterotrimeric G-gamma 1 (Gpg1) participates with G-beta 1 subunits (Gpb1) in the induction of hyphal growth and virulence via the PKA pathway in Mucor lusitanicus.
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Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, 58038 Morelia, Michoacán, Mexico. Electronic address:
Previous work from our lab indicates that the heterotrimeric Gβ subunit 1 (Gpb1) enhances hyphal development and virulence in Mucor lusitanicus. In this study, three Gγ- and two additional Gβ-encoding genes were deleted to identify which ones might have a similar role as Gpb1. Deletion of gpg1 reduces hyphal growth, virulence, cyclic adenosine monophosphate (cAMP) levels, and protein kinase A (PKA) activity, similar to gpb1 deletion, suggesting that gpg1 participates in the same regulatory pathway as gpb1.
View Article and Find Full Text PDFDesign, synthesis, and biological evaluation of novel azaspirooxindolinone derivatives as potent inhibitors of ITK and BTK-dependent cancers.
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Department of Chemistry, School of Science, GITAM University, Hyderabad 502102, Telangana, India. Electronic address:
Interleukin-2-inducible T-cell kinase (ITK) and Bruton's tyrosine kinase (BTK) are two important members of the Tec family with crucial roles in immune system function. Deregulation in ITK and BTK activity is linked to several hematological malignancies, making them key targets for cancer immunotherapy. In this study, we synthesized a series of azaspirooxindolinone derivatives and evaluated their cytotoxic activity against ITK/BTK-negative and positive cancer cell lines, followed by enzymatic inhibition studies to assess the ITK/BTK kinase selectivity of two hit compounds.
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School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 211189, PR China.
Bruton tyrosine kinase (BTK), a non-receptor tyrosine kinase falling within the Tec kinase family, forms an essential part of the B cell receptor (BCR) signaling cascade. It has come to be regarded as a potential drug target for addressing a wide range of diseases, with a particular focus on hematopoietic malignancies and autoimmune disorders related to B lymphocytes. In the present study, by uncovering the binding mechanisms of the inhibitor Orelabrutinib with BTK, we identified four crucial structural elements requisite for the inhibition.
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Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China. Electronic address:
Lipid accumulation in renal tubules is a major determinant of diabetic kidney disease (DKD), and activation of SREBPs plays a central role in this process. Our study aims to explore whether HSPA8, a molecular chaperone, is the master regulator of INSIG/SREBPs function in DKD. Here, we show that tubular epithelial cell (TEC)-specific knockout of HSPA8 upregulates the phosphorylation of INSIG1 and INSIG2, which disrupts the interaction between INSIG proteins and SCAP, leading to SREBP activation.
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