Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies

• Published in: Journal of hematology and oncology Vol. 14; no. 1; pp. 40 - 15
• Main Authors: Gu, Danling, Tang, Hanning, Wu, Jiazhu, Li, Jianyong, Miao, Yi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06.03.2021; BioMed Central; BMC
• Subjects: Adverse events; B cell malignancies; B cells; B-cell receptor; Bruton's tyrosine kinase; BTK; C481 mutations; Cancer; Cardiac arrhythmia; Cell activation; Cell proliferation; Chronic lymphocytic leukemia; Clinical trials; Cysteine; Development and progression; Diarrhea; Drug resistance; Drug therapy; Health aspects; Hematology; Ibrutinib; Infections; Kinases; Lymphatic leukemia; Lymphocytes B; Lymphoma; Medical prognosis; Medical research; Medicine, Experimental; Mutation; Non-covalent inhibitors; Oncology; Phenols; Phosphorylation; Protein-tyrosine kinase; Review; Targeted cancer therapy; Tyrosine; BTK; B cell malignancies; Non-covalent inhibitors; Ibrutinib; C481 mutations
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-021-01049-7

B cell receptor (BCR) signaling is involved in the pathogenesis of B cell malignancies. Activation of BCR signaling promotes the survival and proliferation of malignant B cells. Bruton tyrosine kinase (BTK) is a key component of BCR signaling, establishing BTK as an important therapeutic target. Several covalent BTK inhibitors have shown remarkable efficacy in the treatment of B cell malignancies, especially chronic lymphocytic leukemia. However, acquired resistance to covalent BTK inhibitors is not rare in B cell malignancies. A major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481)  mutations, which disrupt the binding of covalent BTK inhibitors. Additionally, adverse events due to the off-target inhibition of kinases other than BTK by covalent inhibitors are common. Alternative therapeutic options are needed if acquired resistance or intolerable adverse events occur. Non-covalent BTK inhibitors do not bind to C481, therefore providing a potentially effective option to patients with B cell malignancies, including those who have developed resistance to covalent BTK inhibitors. Preliminary clinical studies have suggested that non-covalent BTK inhibitors are effective and well-tolerated. In this review, we discussed the rationale for the use of non-covalent BTK inhibitors and the preclinical and clinical studies of non-covalent BTK inhibitors in B cell malignancies.