Design, Synthesis, and Biological Evaluation of Pyrrolo[1,2-a]quinoxalin-4(5H)-one Derivatives as Potent and Orally Available Noncovalent Bruton’s Tyrosine Kinase (BTK) Inhibitors

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 7, 2025

Bruton's tyrosine kinase (BTK) is a therapeutic target for B-cell-driven malignancies. Most of the approved covalent BTK inhibitors are associated with treatment limitations due to off-target toxicity and drug resistance. Developing noncovalent promising strategy address unmet clinical needs. Here, novel series pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives were designed synthesized as inhibitors. Among them, representative compound 9 exhibited potent inhibitory activity (IC50 = 21.6 nM) excellent selectivity against panel 468 kinases. Moreover, oral exposure property was improved, antitumor efficacy (TGI 64.4%) superior lead S2 28.7%) Ibrutinib 41.1%) in U-937 xenograft models at an dosage 50 mg/kg. All these results suggest that potent, selective, orally available inhibitor worthy further development.

Язык: Английский

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The Development of BTK Inhibitors: A Five-Year Update

Molecules, Год журнала: 2021, Номер 26(23), С. 7411 - 7411

Опубликована: Дек. 6, 2021

Bruton’s tyrosine kinase (BTK) represented, in the past ten years, an important target for development of new therapeutic agents that could be useful cancer and autoimmune disorders. To date, five compounds, able to block BTK irreversible manner, have been launched market, whereas many reversible inhibitors (BTKIs), with reduced side effects are more long-term administration disorders, under clinical investigation. Despite presence literature articles reviews, studies on function BTKIs great interest pharmaceutical companies as well academia. This review is focused compounds appeared from 2017 or manner; also, promising tunable inhibitors, PROTAC molecules, reported. summary improve knowledge chemical diversity provide information future studies, particularly medicinal chemistry point view. Data reported here collected different databases (Scifinder, Web Science, Scopus, Google Scholar, Pubmed) using “BTK” “BTK inhibitors” keywords.

Язык: Английский

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Evaluation of orelabrutinib monotherapy in patients with relapsed or refractory Waldenström's macroglobulinemia in a single-arm, multicenter, open-label, phase 2 study

EClinicalMedicine, Год журнала: 2022, Номер 52, С. 101682 - 101682

Опубликована: Окт. 1, 2022

BackgroundOrelabrutinib is a novel, small molecule, selective irreversible Bruton tyrosine kinase inhibitor. The purpose of this study was to evaluate the efficacy and safety orelabrutinib in patients with relapsed or refractory Waldenström's macroglobulinemia (R/R WM).MethodsThis prospective, multicenter WM who had at least one prior line treatment. Orelabrutinib administered orally daily dose 150 mg until disease progression unacceptable toxicity. primary endpoint major response rate (MRR) assessed by Independent Review Committee (IRC) according IWWM-6. This registered ClinicalTrials.gov, NCT04440059. trial also on Center for Drug Evaluation (www.chinadrugtrials.org.cn) March 2019, number CTR2019036.FindingsBetween August 2019 December 2020, 66 R/R were eligibility. Forty-seven eligible evaluated median follow-up 16.4 months (interquartile range: 12.5, 19.5). As IRC, MRR 80.9%, overall 89.4%. time minor 1.9 months. PFS rates 89.4% 12 For MYD88L265P/CXCR4NEG, MYD88L265P/CXCR4S338X, MYD88NEG/CXCR4NEG mutations, MRRs 84.6%, 100%, 25.0%. Most adverse events Grades 1 2 (91.0%). common grade 3 higher occurring neutropenia (10.6%), thrombocytopenia (6.4%), pneumonia (4.3%). Serious (SAE) occurred 10 (21.3%). One treatment-related death reported (hepatitis B reactivation).InterpretationOrelabrutinib has shown good manageable profiles WM.FundingInnoCare Pharma.

Язык: Английский

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Bruton’s Tyrosine Kinase Inhibition in Multiple Sclerosis

Current Neurology and Neuroscience Reports, Год журнала: 2022, Номер 22(11), С. 721 - 734

Опубликована: Окт. 27, 2022

Язык: Английский

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B cell targeted therapies in inflammatory autoimmune disease of the central nervous system

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Март 9, 2023

Cumulative evidence along several lines indicates that B cells play an important role in the pathological course of multiple sclerosis (MS), neuromyelitisoptica spectrum disorders (NMOSD) and related CNS diseases. This has prompted extensive research exploring utility targeting to contain disease activity these disorders. In this review, we first recapitulate development from their origin bone marrow migration periphery, including expression therapy-relevant surface immunoglobulin isotypes. Not only ability produce cytokines immunoglobulins seems be essential driving neuroinflammation, but also regulatory functions strongly impact pathobiology. We then critically assess studies cell depleting therapies, CD20 CD19 monoclonal antibodies, as well new class modulating substances, Bruton´s tyrosinekinase (BTK) inhibitors, MS, NMOSD MOGAD.

Язык: Английский

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

Therapeutic Advances in Neurological Disorders, Год журнала: 2024, Номер 17

Опубликована: Янв. 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.

Язык: Английский

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New Means and Challenges in the Targeting of BTK

Clinical Cancer Research, Год журнала: 2024, Номер 30(11), С. 2333 - 2341

Опубликована: Апрель 5, 2024

Abstract Bruton's tyrosine kinase (BTK) is central to the survival of malignant and normal B lymphocytes has been a crucial therapeutic target several generations inhibitors newly developed degraders. These new means for targeting BTK have added additional agents armamentarium battling cancers dependent on B-cell receptor (BCR) signaling, including chronic lymphocytic leukemia other non–Hodgkin lymphomas. However, development acquired resistance mutations each these classes led challenges in as well novel insights into BCR signaling. The first-generation covalent inhibitor ibrutinib susceptible affecting binding site, cysteine 481 (C481). Newer noncovalent inhibitors, such pirtobrutinib, overcome C481 mutation–mediated but are domain mutations, particularly at residues Threonine 474 Leucine 528. In addition, shown biochemically patients cause cross-resistance some inhibitors. Importantly, newer generation zanubrutinib acalabrutinib same that confer L528W mutation particular interest it disrupts activity BTK, rendering dead. This observation suggests may act independently its scaffold. Thus, timely degrading proteolysis drugs allowed degradation, rather than just enzymatic inhibition, lymphomas, early clinical trials evaluate degraders underway.

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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Bruton’s Tyrosine Kinase Inhibitors: A New Generation of Promising Agents for Multiple Sclerosis Therapy

Cells, Год журнала: 2021, Номер 10(10), С. 2560 - 2560

Опубликована: Сен. 27, 2021

B cells play a central role in the pathogenesis of multiple sclerosis (MS), as demonstrated through success various cell-depleting monoclonal antibodies. Bruton's tyrosine kinase (BTK) is critical molecule intracellular signaling from receptor and receptors expressed innate immune system. BTK inhibitors may be non-cell-depleting alternative to cell modulation. In this review, structure, signaling, roles are reviewed among different assayed animal models MS clinical trials.

Язык: Английский

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Addition of BTK inhibitor orelabrutinib to rituximab improved anti-tumor effects in B cell lymphoma

Molecular Therapy — Oncolytics, Год журнала: 2021, Номер 21, С. 158 - 170

Опубликована: Апрель 4, 2021

Язык: Английский

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