Imidazopyridine-based kinase inhibitors as potential anticancer agents: A review

Bioorganic Chemistry, Год журнала: 2023, Номер 140, С. 106831 - 106831

Опубликована: Сен. 3, 2023

Язык: 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, Год журнала: 2024, Номер 21(12), С. 867 - 887

Опубликована: Ноя. 1, 2024

Язык: Английский

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Bruton Tyrosine Kinase Degraders

American Journal of Clinical Oncology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 14, 2025

Bruton tyrosine kinase (BTK) is a key enzyme involved in B-cell development and signaling, making it crucial target the treatment of malignancies, such as chronic lymphocytic leukemia non-Hodgkin lymphoma. While BTK inhibitors (BTKi), ibrutinib, have been effective, resistance—both intrinsic acquired—poses significant challenge, often associated with mutations like C481S. To address this, novel degraders developed, leveraging proteolysis-targeting chimeras to selectively degrade both wild-type mutant forms. This approach offers promising strategy overcome BTKi resistance. Agents NRX-0492, BGB-16673, NX-5948, NX-2127, HZ-Q1060, ABBV-101, AC676 shown degradation preclinical early clinical trials. NRX-0492 demonstrated over 90% sustained pharmacodynamic effects, whereas BGB-16673 achieved responses 67% patients relapsed/refractory malignancies. Similarly, NX-5948 NX-2127 showed potent degradation, addition, targeting immunomodulatory proteins, resulting partial stable lymphoma patients. candidate, displayed rapid vivo. Early-phase trials ABBV-101 are also showing results. These favorable safety profiles, manageable adverse events, offer therapeutic avenue for BTKi-resistant As progress, these hold potential significantly enhance outcomes, offering new frontier personalized cancer therapy.

Язык: Английский

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Advances in maintenance therapies for neuromyelitis optica spectrum disorders: a new era of targeted drugs

Multiple Sclerosis and Related Disorders, Год журнала: 2025, Номер 96, С. 106351 - 106351

Опубликована: Фев. 22, 2025

Язык: Английский

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Harnessing p53 for targeted cancer therapy: new advances and future directions

Transcription, Год журнала: 2025, Номер unknown, С. 1 - 44

Опубликована: Март 3, 2025

The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, activates of genes that mediate its tumor-suppressive functions. Distinctive characteristics outlined here enable a well-defined program involved cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well facilitating autoregulation within network. This versatile, anti-cancer network governed chiefly by single protein represents an immense opportunity for targeted cancer treatment, since about half tumors retain unmutated p53. During last two decades, numerous compounds have been developed block interaction with main negative regulator MDM2. However, small molecule inhibitors MDM2 only induce therapeutically desirable apoptotic limited number types. Moreover, clinical trials monotherapies not met expectations revealed hematological toxicity characteristic adverse effect across this drug class. Currently, combination treatments are leading strategy enhancing efficacy reducing effects inhibitors. review summarizes efforts identify test therapeutics work synergistically Two types drugs emerged among used following treatments: first, modulators p53-regulated transcriptome (including chromatin modifiers), translatome, proteome, second, targeting downstream pathways such metabolic immune ferroptosis, growth signaling. Here, we current literature field, while also highlighting overarching principles could guide target selection future treatments.

Язык: Английский

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Comprehensive Characterization of Bruton’s Tyrosine Kinase Inhibitor Specificity, Potency, and Biological Effects: Insights into Covalent and Noncovalent Mechanistic Signatures

ACS Pharmacology & Translational Science, Год журнала: 2025, Номер 8(4), С. 917 - 931

Опубликована: Март 12, 2025

Uncovering a drug's mechanism of action and possible adverse effects are critical components in drug discovery development. Moreover, it provides evidence for why some drugs prove more effective than others how to design better altogether. Here, we demonstrate the utility high-throughput vitro screening platform along with comprehensive panel aid characterization 15 Bruton's tyrosine kinase (BTK) inhibitors that either approved by FDA or presently under clinical evaluation. To compare potency these drugs, measured binding affinity each wild-type BTK as well clinically relevant resistance mutant (BTK C481S). In doing so, discovered considerable difference selectivity proteins. Some this potentially contributes experienced patients undergoing therapy using drugs. Overall, noncovalent showed stronger both when compared covalent inhibitors, majority demonstrating higher specificity less off-target modulation. Additionally, biological outcomes four human cell-based models. As expected, found different phenotypic profiles inhibitor. However, two had fewer inhibitors. This similar in-depth preclinical candidates can provide insights into efficacy compound may affect its safety setting.

Язык: Английский

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Pharmacology and safety of TAS5315, a Bruton tyrosine kinase inhibitor, in healthy volunteers: First‐in‐human, randomized, ascending‐dose studies

British Journal of Clinical Pharmacology, Год журнала: 2025, Номер unknown

Опубликована: Март 14, 2025

Abstract Aim TAS5315 is a Bruton tyrosine kinase (Btk) inhibitor in development for autoimmune and allergic diseases, including rheumatoid arthritis (RA) chronic spontaneous urticaria (CSU). Two clinical studies evaluated the pharmacology safety of single multiple oral doses TAS5315. Methods phase 1 (single ascending‐dose [SAD] [MAD]) assessed pharmacokinetics (including effect food), pharmacodynamics (Btk occupancy, inhibition basophil activation) (up to 8 mg/day) healthy males. Results showed linear over 0.01‐8 mg dose range; maximum plasma concentration area under concentration‐time curve were reduced by ~40% food. had dependent effects on Btk activation. In SAD study, ≥2 resulted mean occupancy almost 100% at 2 6 h, >80% 24 post‐administration. 1‐8 mg/day inhibited activation (mean change from baseline −55% −89%). was generally tolerable. Although it dose‐dependently platelet aggregation (over 2‐8 both studies) prolonged bleeding time (1‐8 MAD study), no relationship between these symptoms observed. All adverse drug reactions mild resolved without treatment; noteworthy concerns observed either study. Conclusion These data indicate has potential as novel therapeutic immunological diseases associated with aberrant signalling, RA CSU. Further evaluation warranted.

Язык: Английский

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Myeloid-Derived Suppressor Cells: Implications in Cancer Immunology and Immunotherapy

Frontiers in Bioscience-Landmark, Год журнала: 2025, Номер 30(3)

Опубликована: Март 20, 2025

Myeloid-derived suppressor cells (MDSCs) are believed to be key promoters of tumor development and recognized as a hallmark cancer cells’ ability evade the immune system evasion. MDSC levels often increase in peripheral blood microenvironment (TME). These exert immunosuppressive functions, weakening anticancer surveillance system, part by repressing T-cell immunity. Moreover, MDSCs may promote progression interact with cells, increasing expansion favoring an immunotolerant TME. This review analyzes primary roles immunity, discusses urgent need develop effective MDSC-targeted therapies, highlights potential synergistic combination targeting chimeric antigen receptors checkpoint inhibitors.

Язык: Английский

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Pharmacological profiling in CLL patients during pirtobrutinib therapy and disease progression

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 31, 2025

Pirtobrutinib is a reversible Bruton’s tyrosine kinase (BTK) inhibitor that has shown efficacy for patients with chronic lymphocytic leukemia (CLL) in BRUIN trial. These were previously treated covalent BTK (cBTKi) and either discontinued cBTKi or had disease progression during therapy. As result, some wild-type while others mutant (mostly C481 site where binds). All received pirtobrutinib monotherapy. Twenty-six CLL from at MD Anderson twenty-three followed up least two years. We compared baseline features between who progressive-disease versus those remained on therapy the first 24 cycles of performed pharmacological profiling peripheral blood mononuclear cells taken pretreatment, therapy, progression. Relapsed/refractory to prior cBTKi, mutations, unmutated IGHV, bulky lymph nodes, XPO1 mutation complex karyotype more prevalent attributes subgroup. Interestingly, among progressive-disease, only three BTK, eleven C481). reported before, we also observed C481S clone was decreased T474 developed increased. did samples when responsive primary are sensitive pirtobrutinib. analyzed sensitivity other targeted clinically available agents patient PD needed new treatment regimen. Ex vivo pharmacologic suggested (CLL cells) became resensitized ibrutinib agents. Combination including venetoclax, effective regardless genomic background even after relapse

Язык: Английский

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Molecular Subtypes and Targeted Therapeutic Strategies in Small Cell Lung Cancer: Advances, Challenges, and Future Perspectives

Molecules, Год журнала: 2025, Номер 30(8), С. 1731 - 1731

Опубликована: Апрель 12, 2025

Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid progression, early metastasis, and high recurrence rates. Historically considered homogeneous disease, recent multi-omic studies have revealed distinct molecular subtypes driven lineage-defining transcription factors, including ASCL1, NEUROD1, POU2F3, YAP1, as well an inflamed subtype (SCLC-I). These exhibit unique therapeutic vulnerabilities, thereby paving the way for precision medicine targeted therapies. Despite advances in classification, tumor heterogeneity, plasticity, therapy resistance continue to hinder clinical success treating SCLC patients. To this end, novel strategies are being explored, BCL2 inhibitors, DLL3-targeting agents, Aurora kinase PARP epigenetic modulators. Additionally, immune checkpoint inhibitors (ICIs) show promise, particularly immune-enriched of Hence, deeper understanding characteristics, evolution, regulatory mechanisms subtype-specific factors crucial rationally optimizing therapy. This knowledge not only facilitates identification targets, but also provides foundation overcoming developing personalized combination treatment strategies. In future, integration data, dynamic monitoring, approaches expected further advance translation therapies, ultimately improving patient survival outcomes.

Язык: Английский

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