Review of the development of BTK inhibitors in overcoming the clinical limitations of ibrutinib

Ran, Fansheng; Liu, Yun; Wang, Chen; Xu, Zhongyuan; Zhang, Yanan; Liu, Yang; Zhao, Guisen; Ling, Yong

doi:10.1016/j.ejmech.2021.114009

Cited by 45 publications

(29 citation statements)

References 139 publications

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“…Covalent inhibitors bind to the wild-type (WT) or mutant cysteine 481 (Cys481) residue via covalent bonding. Non-covalent inhibitors can occupy the ATP binding pocket or a specific H3 pocket of BTK via non-covalent forces like hydrogen bonding or hydrophobic interactions [ 57 ]. All the currently approved agents belong to irreversible covalent inhibitors that could potently and persistently inhibit the enzyme activity of BTK (Fig.…”

Section: An Overview Of Btk Inhibitorsmentioning

confidence: 99%

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Alu

Han

et al. 2022

J Hematol Oncol

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Bruton’s tyrosine kinase (BTK) is an essential component of multiple signaling pathways that regulate B cell and myeloid cell proliferation, survival, and functions, making it a promising therapeutic target for various B cell malignancies and inflammatory diseases. Five small molecule inhibitors have shown remarkable efficacy and have been approved to treat different types of hematological cancers, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib. The first-in-class agent, ibrutinib, has created a new era of chemotherapy-free treatment of B cell malignancies. Ibrutinib is so popular and became the fourth top-selling cancer drug worldwide in 2021. To reduce the off-target effects and overcome the acquired resistance of ibrutinib, significant efforts have been made in developing highly selective second- and third-generation BTK inhibitors and various combination approaches. Over the past few years, BTK inhibitors have also been repurposed for the treatment of inflammatory diseases. Promising data have been obtained from preclinical and early-phase clinical studies. In this review, we summarized current progress in applying BTK inhibitors in the treatment of hematological malignancies and inflammatory disorders, highlighting available results from clinical studies.

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Section: An Overview Of Btk Inhibitorsmentioning

confidence: 99%

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Alu

Han

et al. 2022

J Hematol Oncol

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“…Acquired resistance to covalent inhibitors is observed in approximately 60% of longterm treated patients with CLL [96,97]. In most cases, BTK resistance is caused by the development of clones with mutated cysteine (C481) in the ibrutinib binding site [98,99].…”

Section: Resistance To Btk Inhibitorsmentioning

confidence: 99%

“…Several strategies for overcoming resistance to BTK have been investigated [97]. In particular, the third-generation, reversible, noncovalent BTK inhibitors display inhibitory activities against both BTK and BTKC481 mutants and have the potential to overcome resistance to covalent inhibitors caused by BTKC481 mutation [101].…”

Section: Resistance To Btk Inhibitorsmentioning

confidence: 99%

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

Robak

Witkowska

Smolewski

2022

Cancers

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The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib was the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies have evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in early-phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, and drug–drug interactions associated with the treatment of CLL with BTK inhibitors and examines their further implications.

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“…Reversible BTKis can be divided into covalent reversible inhibitors and non-covalent reversible inhibitors ( Table 2 ), with the two acting through different mechanisms: the non-covalent inhibitors do not bind to the C481 site on BTK. They hence provide an effective alternative to patients with B-cell malignancies who have developed resistance following prior therapy with covalent BTKis [ 57 , 58 ].…”

Section: Characteristics Of Btk Inhibitorsmentioning

confidence: 99%

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

Robak

2022

JCM

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The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management of patients with B-cell lymphoid malignancies. BTK is an important molecule that interconnects B-cell antigen receptor (BCR) signaling. BTK inhibitors (BTKis) are classified into three categories, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors. Ibrutinib is the first covalent, irreversible BTK inhibitor approved in 2013 as a breakthrough therapy for chronic lymphocytic leukemia patients. Subsequently, two other covalent, irreversible, second-generation BTKis, acalabrutinib and zanubrutinib, have been developed for lymphoid malignancies to reduce the ibrutinib-mediated adverse effects. More recently, irreversible and reversible BTKis have been under development for immune-mediated diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, pemphigus vulgaris, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s disease, and chronic spontaneous urticaria, among others. This review article summarizes the preclinical and clinical evidence supporting the role of BTKis in various autoimmune, allergic, and inflammatory conditions.

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Review of the development of BTK inhibitors in overcoming the clinical limitations of ibrutinib

Cited by 45 publications

References 139 publications

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

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