Bruton tyrosine kinase btk is expressed in blymphocytes, myeloid cells and platelets, and btkinhibitors btki are used to treat patients with bcell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs. The firstgeneration inhibitor ibrutinib works by covalent irreversible binding to btk, a nonreceptor tyrosine kinase of the tec transient erythroblastopenia of childhood family that plays a critical role in the bcell receptor signaling pathway. Brutons tyrosine kinase abbreviated btk or btk, also known as tyrosineprotein kinase btk, is a tyrosine kinase that is encoded by. Cancers free fulltext role of brutons tyrosine kinase. The effect of brutons tyrosine kinase btk inhibitors on. Transphosphorylation of brutons tyrosine kinase on tyrosine 551. Inhibition of brutons tyrosine kinase btk with the irreversible inhibitor ibrutinib has emerged as a transformative treatment option for patients with chronic lymphocytic leukemia cll and other bcell malignancies, yet 80% of cll patients develop resistance due to a cysteine to serine mutation at the site covalently bound by ibrutinib c481s. B would then induce transcription of the bkt gene and inhibit apoptosis. Prognosis for patients following relapse is poor, and treatment choices are limited.
Jun 28, 2001 mutations in brutons tyrosine kinase btk gene result in x linked agammaglobulinemia xla. Tang 2, carl campos 2, derrek schartz 2, paolo codega 2, donna nichol 2. Brutons tyrosine kinase btk inhibitor pipeline insight. Hem strin homology ph domain missense mutation gluta agglutinin mate 41 1 lysine, designated btk, was found. Current status of brutons tyrosine kinase inhibitor. Bruton tyrosine kinase btk is a nonreceptor tyrosine kinase that plays a central role in the signal transduction of the bcell antigen receptor and other cell surface receptors, both in normal and malignant b lymphocytes. Our earlier results revealed that bruton s tyrosine kinase btk associates with bright to form a dnabinding complex. Pdf brutons tyrosine kinase btk is intimately involved in multiple. Brutons tyrosine kinase btk is critical for b cell proliferation and activation, and the development of btk inhibitors is a vigorously pursued strategy for the treatment of various b cell malignancies. Research article ibrutinib unmasks critical role of bruton tyrosine kinase in primary cns lymphoma christian grommes 1, 2, 3, alessandro pastore 4, nicolaos palaskas 2, sarah s. Brutons tyrosine kinase regulates immunoglobulin promoter.
Recent studies, however, have focused on its role in regulating innate immune responses in myeloid cells, acting downstream of tlr4 and the antiviral tlrs, tlr3, 7. Brutons tyrosine kinase btk is critical for bcell proliferation and. The free energy difference of the transition between the two saraste. The brutons kinase inhibitors currently available are as follows. Brutons tyrosine kinase activity is negatively regulated by. Dermatological toxicities of brutons tyrosine kinase. A phase 2 study of the effect of the bruton s tyrosine kinase inhibitor ibrutinib on disease response in patients with high risk smoldering multiple myeloma pi. Achieving brutons tyrosine kinase btk inhibition beigene. Brutons tyrosine kinase btk, a member of the tec family of protein tyrosine kinases ptks, plays a vital and diverse function in many cellular processes. Ibrutinib pci32765 is the most advanced btk inhibitor in clinical testing, with ongoing phase iii clinical trials in patients with chronic lymphocytic. Structurebased drug design of rn486, a potent and selective. Receive free emailalerts when new articles cite this article. Using single strand conformation polymorphism sscp followed by direct sequencing 21 mutations were found in 27 patients with an xla phenotype from 21 unrelated families.
Brutons tyrosine kinase is a tec family tyrosine kinase expressed in b and myeloid cells. Abstract bruton s tyrosine kinase btk, a tec family nonreceptor tyrosine kinase that is required for b cell development, is critical for the initiation and maintenance of human b cell malignancies. Current clinical practice is continuous longterm administration of btki, which can be complicated by. Recent studies, however, have focused on its role in regulating innate immune responses in myeloid cells, acting downstream of. Targeting bruton tyrosine kinase using noncovalent. Brutons tyrosine kinase btk is a member of the tec non receptor. Btk is also phosphorylated on threonine residues in a pkcdependent manner and associates with pkc.
Bruton s agammaglobulinemia tyrosine kinase btk is a cytoplasmic tyrosine kinase important in blymphocyte development, differentiation, and signaling. Brutons tyrosine kinase inhibitors are breakthrough drugs that have been approved to treat many b cell malignancies. Aug 01, 2019 brutons tyrosine kinase btk is a nonreceptor tyrosine kinase. Inhibitor of bruton s tyrosine kinase a c yuqin song 1, keshu zhou 2, dehui zou 3, jianfeng zhou 4, jiandahu 5, haiyan yang 6, huilaizhang 7,jieji 8, wei xu 9, jie jin 10, fangfang lv 11, ru feng 12, sujun gao , haiyi guo 14, lei zhou 15, rebecca elstrom 16. Brutons tyrosine kinase btk is involved in the immune response and its deficiency impairs b cell maturation. In the current report, we identified brutons tyrosine kinase btk as a functional hi. All three major subfamilies of mitogenactivated protein map kinases, i. Bruton s tyrosine kinase is also known as tyrosine protein kinase.
It is expressed throughout b cell and myeloid development but it is not expressed in nonhematopoietic cells. Brutons tyrosine kinase an overview sciencedirect topics. The covalent bruton tyrosine kinase btk inhibitor ibrutinib is highly efficacious against multiple bcell malignancies. One such target is bruton s tyrosine kinase btk, a tec family kinase member found near the cell membrane that is involved in upstream bcr signaling. Brutons tyrosine kinase is intimately involved in signal transduction pathways. Brutons tyrosine kinase btk inhibitors competitive. Inhibitors targeting brutons tyrosine kinase in cancers.
Bruton tyrosine kinase btk is present in a wide variety of cells and may thus have. Structural mechanism for brutons tyrosine kinase activation at the. Bruton s tyrosine kinase is intimately involved in signal transduction pathways regulating survival, activation, proliferation, and differentiation of b lineage lymphoid cells. We now report that bright coprecipitates with brutons tyrosine kinase btk, the defective enzyme in xlinked. It took approximately 20 years from target discovery to new drug approval. Brutons tyrosine kinase is at the crossroads of metabolic adaptation. Targeting bruton tyrosine kinase using noncovalent inhibitors in b cell malignancies danling gu1,2, hanning tang 1,2, jiazhu wu 1,2, jianyong li1,2,3 and yi miao1,2,3 abstract b cell receptor bcr signaling is involved in the pathogenesis of b cell malignancies. Targeting the c481s ibrutinibresistance mutation in. We evaluated the expression of a novel btk isoform, p65btk, in colorectal cancer crc, to identify its impact on survival. Btk is a member of the tec family of tyrosine kinases and plays an important role in intracellular signaling in activated b cells. Molecular analysis of brutons tyrosine kinase gene in spain. Brutons tyrosine kinase btk is a member of the tec family of nonreceptor protein tyrosine kinases originally described for its role in b cell development 5.
Structural mechanism for brutons tyrosine kinase activation. Bruton tyrosine kinase btk is a tecfamily nonreceptor tyrosine kinase that signals downstream of numerous cellular receptors, including the bcell receptor bcr, tolllike receptors, and fc receptors. Wo2008039218a3 inhibitors of brutons tyrosine kinase. Structurebased drug design was used to guide the optimization of a series of selective btk inhibitors as potential treatments for rheumatoid arthritis. Phase iii study of tirabrutinib, a secondgeneration. Brutons tyrosine kinase inhibitors for mature bcell neoplasms. A detailed picture of the brutons tyrosine kinase btk inhibitor pipeline landscape is provided, which includes the topic overview and brutons tyrosine kinase btk. Ibrutinib unmasks critical role of bruton tyrosine kinase. Like src, btk has a carboxyterminal catalytic domain adjacent to sh2 and sh3 src homology 2 and 3 domains. Secondgeneration inhibitors of bruton tyrosine kinase jingjing wu1, christina liu2, stella t. Rfreeis the same as rcryst but only includes 5% of data excluded from. Dec 01, 2020 brutons tyrosine kinase inhibitors, which are small molecule agents that bind to the intracellular domain of the brutons kinase protein. Mar 31, 2021 glucocorticoid therapy resistance in bcell malignancies is often associated with constitutive activation of tyrosine kinases.
Xla is caused by a mutation on the x chromosome xq21. Brutons tyrosine kinase btk, a nonreceptor tyrosine kinase member of the tec kinase family, plays a significant role in bcell development and is a unique therapeutic target in bcell malignancies. Pdf novel brutons tyrosine kinase inhibitors currently in. Btk is expressed throughout b cell development, widely participating in multiple signal pathways including pi3k, plc. When the gene responsible for xla was identified in 1993, it was named bruton s tyrosine kinase btk in honor of dr. Oct 29, 2020 brutons tyrosine kinase btk inhibitor is a promising novel agent that has potential efficiency in bcell malignancies. Treatment of patients with relapsed or refractory mantlecell. Bruton tyrosine kinase then phosphorylates phospholipasec. Here, we conducted a phase iii study of tirabrutinib, a secondgeneration, potent, selective brutons tyrosine kinase inhibitor, in relapsed or refractory pcnsl. Ability of brutons tyrosine kinase inhibitors to sequester.
Brutons tyrosine kinase btk is expressed in a variety of hematopoietic cells. Novel anticancer drugs targeting hyperactivated tyrosine kinases, such as brutons tyrosine kinase btk, have, therefore, gained much interest over the past few decades and have already been approved for clinical use. We evaluated the efficacy and safety of zanubrutinib, an investigational selective bruton s tyrosine kinase btk inhibitor. Development of the brutons tyrosine kinase inhibitor. Bruton tyrosine kinase inhibition journal of allergy and clinical. Brutons tyrosine kinase btk activation on the cell membrane is critical for b cell proliferation and development, and btk inhibition is a promising treatment for several hematologic cancers and autoimmune diseases. The bcell receptor signaling pathway as a therapeutic target in cll. The biological function of btk in several bcell lymphoid malignancies has led to the development of the oral btk inhibitor ibrutinib. Bruton tyrosine kinase btk is a 659 amino acid member of a recently identified subfamily of srcrelated cytoplasmic tyrosine kinases figure 1.
May 28, 2014 original article the new england journal of medicine 2286 n engl j med 370. Btk was initially shown to be defective in the primary immunodeficiency xlinked agammaglobulinemia xla and is essential both for b cell development and function of mature b cells. Feb 19, 2018 brutons tyrosine kinase btk is a nonreceptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many b cell malignancies. The evolving role of brutons tyrosine kinase inhibitors. Inhibition of the bruton tyrosine kinase pathway in bcell. Bruton s tyrosine kinase bruton s tyrosine kinase btk is a key component of the bcell receptor bcr signaling pathway and plays an essential role in bcell maturation and lymphomagenesis. Abstract hypoxia induced mitogenic factor himf is a member of the. Cardiovascular toxicities of brutons tyrosine kinase. Pdf role of brutons tyrosine kinase inhibitors in hiv1. Mutations in the btk gene lead to xlinked agammaglobulinemia xla in humans and xlinked immunodeficiency xid in mice. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10fold increase in activity. Concurrent optimization of druglike properties led to compound 1 rn486 j.
Crystal structure of brutons tyrosine kinase domain suggests a. Jul 30, 2019 compare and contrast the brutons tyrosine kinase btk inhibitors, including their pharmacological differences discuss key published clinical trials, ongoing clinical trials, and guideline recommendations for btk inhibitors in mantle cell lymphoma mcl and chronic lymphocytic leukemia cll. This revealed a synergistic effect of btk inhibitors on dau cytotoxicity in. Ogden bruton in a groundbreaking research paper published in 1952 describing a boy unable to develop immunities to common childhood diseases and. Abstract bruton tyrosine kinase btk links the bcell antigen receptor bcr and tolllike receptors with nfb. Initial strategies involving the use of systemic chemotherapies have been gradually replaced by more targeted therapies to improve survival and overall tolerability. Covalent cysteine targeting of brutons tyrosine kinase. Pdf brutons tyrosine kinase btk, a member of the tec family of protein tyrosine kinases ptks, plays a vital and diverse function in many. Disclosed herein are compounds that form covalent bonds with bruton s tyrosine kinase btk. Brutons tyrosine kinase is required for apoptotic cell.
Brutons tyrosine kinase wiktionary, the free dictionary. Interaction of brutons tyrosine kinase and protein kinase c. Brutons tyrosine kinase inhibitors for mature bcell. Ibrutinib is an irreversible inhibitor of bruton s tyrosine kinase btk and is effective in chronic lymphocytic leukemia cll. Ibrutinibs mechanism of action specifically targets cancerous cells, and its once. Protein kinase inhibitors as sensitizing agents for chemotherapy, 2019. Acalabrutinib calquence brutons tyrosine kinase btk mcl, cllsll.
However, it is not selective for btk, and multiple mechanisms of resistance, including the c481sbtk mutation, can compromise its efficacy. Maximum tolerated dose was not reached at 480 mg in the 28day phase i part. Frontiers brutons tyrosine kinase, a component of b cell. Methods of using the btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the. Targeting the c481s ibrutinibresistance mutation in brutons. This retrospective study evaluated 87 consecutive stage iii crc patients treated at the national cancer institute of aviano 19992017. The development of brutons tyrosine kinase btk inhibitors represents a major breakthrough in the treatment of chronic lymphocytic leukemia and other b cell malignancies. Methods for the preparation of the compounds are disclosed.
A detailed mechanistic understanding of btk activation has, however, been lacking. Bruton tyrosine kinase inhibitors are particularly active in patients with cll and mcl, but also received approval for waldenstrom macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma, and chronic graftversushost disease. Protein in immunodeficiency disease with brutons tyrosine kinase. Structural mechanism for brutons tyrosine kinase activation at the cell membrane qi wanga,1, yakov pecherskya, shiori sagawaa, albert c. Bruton s tyrosine kinase btk is a key component of the bcell receptor bcr signaling pathway and plays an essential role in bcell maturation and lymphomagenesis. Those pathways play critical functions in cell proliferation. Brutons tyrosine kinase btk is a nonreceptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and. Covalent cysteine targeting of brutons tyrosine kinase btk. Brutons tyrosine kinase btk activation on the cell membrane is critical for b cell. Ibrutinib unmasks critical role of bruton tyrosine kinase in. We hypothesized that smallmoleculeinduced btk degradation may overcome some of the limitations of traditional enzymatic inhibitors. We performed a phase i clinical trial with ibrutinib, the fi rstinclass btk inhibitor, for patients with relapsed or refractory cns lymphoma. Brutons tyrosine kinase btk is a binding partner for hypoxia.
Treatment of patients with relapsed or refractory mantle. A phase 2 study of the effect of the bruton s tyrosine. Bruton tyrosine kinase degradation as a therapeutic. Brutons tyrosine kinase btk is a cytoplasmic tyrosine kinase that is crucial for. Brutons tyrosine kinase regulates apoptosis and jnksapk. Brutons tyrosine kinase btk inhibitor pipeline insight, 2020.
Here, we examine btk activation using the results of longtimescale molecular dynamics simulations. It has become an attractive drug target because its inhibition may provide significant. Jun 30, 2020 there has been a significant shift in the management of b cell malignancies over the past decade. Mutations in the human btk gene are the cause of xlinked agammaglobulinemia, a male immune deficiency disorder characterized by a lack of mature, immunoglobulin. At first, it was identified as the defective protein in human xlinked agammaglobulinemia xla and is also called bcell. Overview of all the structural information available in the pdb for uniprot. This retrospective study evaluated 87 consecutive stage iii crc patients treated at the national cancer institute of aviano. Nlrp3 inflammasome is activated, it has been reported to require. Pdf the development of brutons tyrosine kinase btk. Tsui3 and delong liu1 abstract bruton tyrosine kinase btk is a critical effector molecule for b cell development and plays a major role in lymphoma genesis.
In humans, loss of function mutations in btk result in xlinked agammaglobulinemia xla, which is character. Terreic acid, a quinone epoxide inhibitor of brutons. Btk has been demonstrated to regulate signaling downstream of the bcell receptor bcr, fc receptors fcrs, and tolllike receptors. Brutons tyrosine kinase btk inhibitor pipeline insight, 2020 report outlays comprehensive insights of present scenario and growth prospects across the mechanism of action. Phase iii study of tirabrutinib, a secondgeneration bruton. Hm71224, a selective brutons tyrosine kinase inhibitor. Treatment of patients with relapsed or refractory mantle cell. Mantlecell lymphoma mcl is an incurable mature bcell neoplasm with high initial response rates followed almost invariably by relapse. The samples were free from phosphorylation at tyr551 of the activation loop as well. Also disclosed are pharmaceutical compositions that include the compounds. Notably, ibrutinibresistant cll lymphocytes were re. Secondgeneration inhibitors of bruton tyrosine kinase. The role of btk in primary central nervous system cns. Bcell antigen receptor signaling is activated in secondary lymphatic organs and drives the proliferation of malignant b cells, including chronic lymphocytic leukemia cll.
Bruton tyrosine kinase, however, plays also a dual function as it can mediate apoptosis through p38 mitogenactivated protein kinase. Role of brutons tyrosine kinase in b cells and malignancies. Mutations in the btk gene lead to xlinked agammaglobulinemia xla. The expression of btk is selectively downregulated in t lymphocytes and plasma cells and the relative level of btk expression may be.
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