In recent years, Bruton tyrosine kinase (BTK) inhibitors have provided significant advances in the treatment of patients with B-cell malignancies. Ibrutinib was the first BTK inhibitor to be approved, and it changed the standard-of-care treatment for diseases such as chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia, improving efficacy outcomes and safety compared to chemotherapy. In this article, we review the development of zanubrutinib, a next-generation BTK inhibitor, from molecular design to patient-related outcomes. We start this journey by providing insights into the discovery of BTK and the physiologic, genetic, and molecular characterization of patients lacking this kinase, together with the brief treatment landscape in the era of chemo-immunotherapies. Zanubrutinib was originally developed by applying a structure-activity strategy to enhance the specificity as well as enzymatic and pharmacokinetic properties. Preclinical studies confirmed greater specificity and better bioavailability of zanubrutinib compared with that of ibrutinib, which supported the initiation of clinical trials in humans. Preliminary clinical results indicated activity in B-cell malignancies together with an improved safety profile, in line with less off-target effects described in the preclinical studies. The clinical program of zanubrutinib has since expanded significantly, with ongoing studies in a wide range of hemato-oncological diseases and in combination with many other therapies. Zanubrutinib currently is approved for various B-cell malignancies in multiple countries. This story highlights the importance of multidisciplinary collaborative research, from bench to bedside, and provides an example of how the commitment to finding improved treatment options should always run parallel to patient care.
近年来，布鲁顿酪氨酸激酶（BTK）抑制剂为B细胞恶性肿瘤患者的治疗带来了显著进展。伊布替尼作为首个获批的BTK抑制剂，改变了慢性淋巴细胞白血病、套细胞淋巴瘤、边缘区淋巴瘤及华氏巨球蛋白血症等疾病的标准治疗模式，与化疗相比在疗效和安全性方面均有所改善。本文回顾了新一代BTK抑制剂泽布替尼从分子设计到患者相关结局的发展历程。我们首先概述BTK的发现过程、缺乏该激酶患者的生理学、遗传学及分子特征，以及化学免疫疗法时代的治疗格局简况。泽布替尼的研发最初采用构效关系策略，旨在提升其特异性、酶学特性及药代动力学性质。临床前研究证实，与伊布替尼相比，泽布替尼具有更高的特异性和更好的生物利用度，这为其后续开展人体临床试验奠定了基础。初步临床结果显示，泽布替尼对B细胞恶性肿瘤具有活性，且安全性更优，这与临床前研究中观察到的脱靶效应减少特征相符。此后，泽布替尼的临床研究项目迅速扩展，目前已在多种血液肿瘤领域开展多项研究，并探索其与多种疗法的联合应用。目前泽布替尼已在多个国家获批用于治疗多种B细胞恶性肿瘤。这一历程凸显了从实验室到临床的多学科合作研究的重要性，并为如何在持续优化治疗方案的同时始终以患者照护为核心提供了范例。
肿瘤(癌症)患者之家