Abstract：
Bruton\'s tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR) signaling pathway, crucial for B-cell survival and proliferation. The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects. Second-generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti-CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis-targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK-targeted therapies provide hope for improved outcomes in patients with B-cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.
摘要：
布鲁顿的酪氨酸激酶（BTK）抑制剂彻底改变了B细胞恶性肿瘤的治疗。他们瞄准BTK,B细胞受体（BCR）信号通路的关键效应，对B细胞存活和增殖至关重要。一流的不可逆BTK抑制剂，伊布替尼,已被批准用于各种B细胞恶性肿瘤，但由于脱靶效应而受到限制。第二代抑制剂,如阿卡拉布替尼和扎努布替尼，提供改进的选择性和减少的副作用。然而,对BTK抑制剂的抗性，由BTK突变驱动，仍然是一个挑战。与PI3K抑制剂的组合疗法，免疫检查点抑制剂，BH3模拟物,和抗CD20抗体在克服抗性方面显示出希望。非共价BTK抑制剂和蛋白水解靶向嵌合体(PROTACs)是具有对抗抗性潜力的新兴策略。总的来说,BTK靶向治疗的进展为改善B细胞恶性肿瘤患者的预后提供了希望,也为解决耐药性提供了有希望的途径.需要进一步的研究来优化组合疗法并确定最佳治疗方案。
