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

Journal of Hematology & Oncology

Hanning Tang¹  Danling Gu¹  Jiazhu Wu¹  Yi Miao²  Jianyong Li² 

[1] Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 210029, Nanjing, China;Key Laboratory of Hematology of Nanjing Medical University, 210029, Nanjing, China;Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 210029, Nanjing, China;Key Laboratory of Hematology of Nanjing Medical University, 210029, Nanjing, China;Pukou CLL Center, 210000, Nanjing, China;

关键词: BTK;    B cell malignancies;    Ibrutinib;    C481 mutations;    Non-covalent inhibitors;   

DOI  :  10.1186/s13045-021-01049-7

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY