RSC Chemical Biology, Год журнала: 2025, Номер unknown
Опубликована: Янв. 1, 2025
Development of a novel fluorescent probe for endogenous BTK imaging using evobrutinib as scaffold. Evo-2 enabled real-time visualisation dynamics in living cells while preserving its enzymatic activity.
Язык: Английский
Molecules, Год журнала: 2023, Номер 28(5), С. 2400 - 2400
Опубликована: Март 6, 2023
In the last few decades, there has been a growing interest in Bruton’s tyrosine kinase (BTK) and compounds that target it. BTK is downstream mediator of B-cell receptor (BCR) signaling pathway affects proliferation differentiation. Evidence demonstrating expression on majority hematological cells led to hypothesis inhibitors (BTKIs) such as ibrutinib can be an effective treatment for leukemias lymphomas. However, body experimental clinical data demonstrated significance BTK, not just malignancies, but also solid tumors, breast, ovarian, colorectal, prostate cancers. addition, enhanced activity correlated with autoimmune disease. This gave rise beneficial therapy rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjögren’s syndrome (SS), allergies, asthma. this review article, we summarize most recent findings regarding well advanced have developed date their applications mainly cancer chronic inflammatory disease patients.
Язык: Английский
Процитировано
42
Nature Communications, Год журнала: 2024, Номер 15(1)
Опубликована: Янв. 4, 2024
Targeted protein degradation (TPD) mediates level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only few have been utilized TPD. Interestingly, the workhorse ligase CRBN observed be downregulated settings resistance immunomodulatory inhibitory drugs (IMiDs). Here we show that essential receptor DCAF1 can harnessed utilizing selective, non-covalent binder. We confirm this binder functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical genetic rescue experiments validate specific via CRL4
Язык: Английский
Процитировано
37
Journal of Hematology & Oncology, Год журнала: 2025, Номер 18(1)
Опубликована: Янв. 13, 2025
The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, signaling molecules that interact promote growth therapeutic resistance. Elucidating the intricate interactions between cells TME crucial in understanding progression challenges. A critical process induced by epithelial-mesenchymal transition (EMT), wherein epithelial acquire mesenchymal traits, which enhance their motility invasiveness progression. By targeting various components TME, novel investigational strategies aim disrupt TME's contribution EMT, thereby improving efficacy, addressing resistance, offering a nuanced approach therapy. This review scrutinizes key players emphasizing avenues therapeutically components. Moreover, article discusses implications for resistance mechanisms highlights current toward modulation along with potential caveats.
Язык: Английский
Процитировано
10
Biomarker Research, Год журнала: 2022, Номер 10(1)
Опубликована: Ноя. 23, 2022
Abstract Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved the life expectancy for patients with refractory or relapse B lymphoma. As acute lymphoblastic leukemia (B-ALL), although primary response rate is promising, high incidence of early caused modest long-term survival CAR-T alone. One main challenges limited persistence cells. To further optimize clinical effects cells, many studies have focused on modifying CAR structure and regulating differentiation. In this review, we focus summarize latest progress strategies adopted during in vitro culture stage to immunotherapy by improving persistence. Such include choosing a suitable source, conditions, combining cells conventional drugs, applying genetic manipulations, all which may improve hematologic malignancies reducing probability recurrence after infusion provide clues solid tumor development.
Язык: Английский
Процитировано
52
Molecules, Год журнала: 2023, Номер 28(7), С. 3043 - 3043
Опубликована: Март 29, 2023
The mammalian bromodomain and extra-terminal domain (BET) family of proteins consists four conserved members (Brd2, Brd3, Brd4, Brdt) that regulate numerous cancer-related immunity-associated genes. They are epigenetic readers histone acetylation with broad specificity. BET linked to cancer progression due their interaction cellular including chromatin-modifying factors, transcription modification enzymes. spectacular growth in the clinical development small-molecule inhibitors underscores interest importance this protein as an anticancer target. Current approaches targeting for therapy rely on mimics block bromodomains from binding chromatin. However, bromodomain-targeted agents suffering dose-limiting toxicities because effects other bromodomain-containing proteins. In review, we provided updated summary about evolution inhibitors. design bivalent inhibitors, kinase dual proteolysis-targeting chimeras (PROTACs), Brd4-selective discussed. novel strategy unique C-terminal (ET) its therapeutic significance will also be highlighted. Apart single agent treatment alone, have been combined chemotherapeutic modalities demonstrating favorable outcomes. investigation specific biomarkers predicting efficacy resistance is needed fully realize potential setting.
Язык: Английский
Процитировано
37
Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(2), С. 864 - 884
Опубликована: Янв. 10, 2024
The DNA-encoded library (DEL) discovery platform has emerged as a powerful technology for hit identification in recent years. It become one of the major parallel workstreams small molecule drug along with other strategies such HTS and data mining. For many researchers working DEL field, it increasingly evident that hits leads discovered via screening bind to target proteins unique unprecedented binding modes. This Perspective is our attempt analyze reports purpose providing rigorous useful account modes observed DEL-derived ligands focus on mode novelty.
Язык: Английский
Процитировано
14
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(4), С. 2208 - 2208
Опубликована: Фев. 12, 2024
Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized the landscape for treatment of hematological malignancies, solid tumors, and, recently, autoimmune disorders. The BTK receptor is expressed in several hematopoietic cells such as macrophages, neutrophils, mast cells, and osteoclasts. Similarly, involved signaling pathways chemokine signaling, Toll-like Fc signaling. Due to their unique mechanism, these agents provide a diverse utility variety disease states not limited field malignant hematology are generally well-tolerated.
Язык: Английский
Процитировано
11
Pharmaceuticals, Год журнала: 2024, Номер 17(1), С. 100 - 100
Опубликована: Янв. 11, 2024
PROTAC is a rapidly developing engineering technology for targeted protein degradation using the ubiquitin–proteasome system, which has promising applications inflammatory diseases, neurodegenerative and malignant tumors. This paper gives brief overview of development design principles PROTAC, with special focus on PROTAC-based explorations in recent years aimed at achieving controlled improving bioavailability as well TPD technologies that use other pathways such autophagy lysosomes to achieve degradation.
Язык: Английский
Процитировано
9
Cancer Treatment Reviews, Год журнала: 2023, Номер 117, С. 102568 - 102568
Опубликована: Апрель 26, 2023
The paracaspase MALT1 has emerged as a key regulator of immune signaling, which also promotes tumor development by both cancer cell-intrinsic and -extrinsic mechanisms. As an integral subunit the CARD11-BCL10-MALT1 (CBM) signaling complex, intriguing dual function in lymphocytes. acts scaffolding protein to drive activation NF-κB transcription factors protease modulate cleavage distinct substrates. Aberrant activity is critical for NF-κB-dependent survival proliferation malignant cells, fostered paracaspase-catalyzed inactivation negative regulators canonical pathway like A20, CYLD RelB. Specifically, B cell receptor-addicted lymphomas rely strongly on this function, but survival, metastasis certain solid cancers sensitive inhibition. Beyond this, exercises cell-extrinsic role maintaining immune-suppressive regulatory T (Treg) cells microenvironment (TME). inhibition able convert pro-inflammatory Treg TME cancers, thereby eliciting robust anti-tumor immunity that can augment effects checkpoint inhibitors. Therefore, promoting functions offer unique therapeutic opportunities, motivated potent selective inhibitors currently under pre-clinical clinical evaluation.
Язык: Английский
Процитировано
19
Journal of Allergy and Clinical Immunology, Год журнала: 2023, Номер 153(5), С. 1229 - 1240
Опубликована: Дек. 21, 2023
Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for >6 weeks. Mast cells (MCs) and basophils are the key pathogenic drivers of CSU; their activation results in histamine cytokine release subsequent dermal inflammation. Two overlapping mechanisms MC basophil have been proposed CSU: type I autoimmunity, also called autoallergy, mediated via IgE against various autoallergens, IIb predominantly IgG directed receptor FcεRI FcεRI-bound IgE. Both involve cross-linking downstream signaling pathways may co-occur same patient. In addition, B-cell (BCR) has postulated to play a role CSU by generating autoreactive B autoantibody production. A cornerstone BCR Bruton's tyrosine kinase (BTK), making BTK inhibition clear therapeutic target CSU. The potential application early-generation inhibitors, including ibrutinib, allergic autoimmune diseases limited due unfavorable benefit–risk profile. However, novel inhibitors improved selectivity safety profiles developed under clinical investigation diseases, Phase 2 trials, remibrutinib fenebrutinib demonstrated rapid sustained improvements disease activity. With 3 studies ongoing, it hoped will present effective, well-tolerated option patients antihistamine-refractory CSU, phenotype presents considerable challenge.
Язык: Английский
Процитировано
19