布鲁顿酪氨酸激酶降解剂:当前概念。

IF 1.6 4区 医学 Q4 ONCOLOGY
Giorgi Sabakhtarishvili, Mouza Alshebli, Omer Bajwa, Imad A Tabbara
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引用次数: 0

摘要

布鲁顿酪氨酸激酶(Bruton tyrosine kinase, BTK)是参与b细胞发育和信号传导的关键酶,是治疗b细胞恶性肿瘤(如慢性淋巴细胞白血病和非霍奇金淋巴瘤)的关键靶点。虽然BTK抑制剂(BTKi),如伊鲁替尼(ibrutinib)是有效的,但内在和获得性的耐药带来了重大挑战,通常与BTK突变如C481S有关。为了解决这个问题,新的BTK降解物已经开发出来,利用蛋白水解靶向嵌合体选择性地降解野生型和突变型BTK。这种方法为克服BTKi耐药性提供了一种有希望的策略。NRX-0492、BGB-16673、NX-5948、NX-2127、HZ-Q1060、ABBV-101和AC676等药物在临床前和早期临床试验中显示出明显的BTK降解。NRX-0492表现出超过90%的BTK降解和持续的药效学效应,而BGB-16673在67%的复发/难治性b细胞恶性肿瘤患者中取得了临床反应。同样,NX-5948和NX-2127也能有效降解BTK,此外,NX-2127还能靶向免疫调节蛋白,在慢性淋巴细胞白血病和非霍奇金淋巴瘤患者中产生部分稳定的应答。HZ-Q1060是一种临床前候选药物,在体内表现出快速和持续的BTK降解。ABBV-101和AC676的早期试验也显示出令人鼓舞的结果。这些BTK降解剂具有良好的安全性,不良事件可控,为btki耐药恶性肿瘤患者提供了新的治疗途径。随着临床试验的进展,这些降解物具有显著提高治疗效果的潜力,为个性化癌症治疗提供了新的前沿。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Bruton Tyrosine Kinase Degraders: Current Concepts.

Bruton tyrosine kinase (BTK) is a key enzyme involved in B-cell development and signaling, making it a crucial target in the treatment of B-cell malignancies, such as chronic lymphocytic leukemia and non-Hodgkin lymphoma. While BTK inhibitors (BTKi), such as ibrutinib, have been effective, resistance-both intrinsic and acquired-poses a significant challenge, often associated with BTK mutations like C481S. To address this, novel BTK degraders have been developed, leveraging proteolysis-targeting chimeras to selectively degrade both wild-type and mutant BTK forms. This approach offers a promising strategy to overcome BTKi resistance. Agents such as NRX-0492, BGB-16673, NX-5948, NX-2127, HZ-Q1060, ABBV-101, and AC676 have shown significant BTK degradation in preclinical and early clinical trials. NRX-0492 demonstrated over 90% BTK degradation with sustained pharmacodynamic effects, whereas BGB-16673 achieved clinical responses in 67% of patients with relapsed/refractory B-cell malignancies. Similarly, NX-5948 and NX-2127 showed potent BTK degradation, with NX-2127, in addition, targeting immunomodulatory proteins, resulting in partial and stable responses in chronic lymphocytic leukemia and non-Hodgkin lymphoma patients. HZ-Q1060, a preclinical candidate, displayed rapid and sustained BTK degradation in vivo. Early-phase trials of ABBV-101 and AC676 are also showing promising results. These BTK degraders have demonstrated favorable safety profiles, with manageable adverse events, and offer a novel therapeutic avenue for patients with BTKi-resistant malignancies. As clinical trials progress, these degraders hold the potential to significantly enhance treatment outcomes, offering a new frontier in personalized cancer therapy.

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来源期刊
CiteScore
4.90
自引率
0.00%
发文量
130
审稿时长
4-8 weeks
期刊介绍: ​​​​​​​American Journal of Clinical Oncology is a multidisciplinary journal for cancer surgeons, radiation oncologists, medical oncologists, GYN oncologists, and pediatric oncologists. The emphasis of AJCO is on combined modality multidisciplinary loco-regional management of cancer. The journal also gives emphasis to translational research, outcome studies, and cost utility analyses, and includes opinion pieces and review articles. The editorial board includes a large number of distinguished surgeons, radiation oncologists, medical oncologists, GYN oncologists, pediatric oncologists, and others who are internationally recognized for expertise in their fields.
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