不适合移植的大 B 细胞淋巴瘤二线使用 axicabtagene ciloleucel：ALYCANTE 最终分析
Second-line axicabtagene ciloleucel in large B-cell lymphoma ineligible for transplantation: ALYCANTE final analysis.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
发现一类新型苯二氮䓬类 Cbl-b 抑制剂用于增强抗肿瘤免疫
英文原题：Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity.
查看英文原题
Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
中文摘要
Casitas B系淋巴瘤原癌基因-b（Cbl-b）是一种RING指E3连接酶，负责抑制T细胞、自然杀伤（NK）细胞和B细胞的活化。在Cbl-b缺陷小鼠中观察到的由T细胞和NK细胞活性升高所产生的强效抗肿瘤活性，证明了我们致力于发现Cbl-b抑制剂的努力是合理的，这些抑制剂可能在免疫肿瘤学中展现出治疗前景，在该领域中免疫系统的激活可以驱动对癌细胞的识别和杀伤。我们开展了一项高通量筛选活动，随后进行了结构辅助的优化，以开发一系列新型苯二氮䓬类强效Cbl-b抑制剂。该系列表现出纳摩尔水平的生化效力以及强效的T细胞活化。这类Cbl-b抑制剂的功能活性通过基于泛素的细胞实验得到了进一步证实。
展开英文摘要原文
Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that is responsible for repressing T-cell, natural killer (NK) cell, and B-cell activation. The robust antitumor activity observed in Cbl-b deficient mice arising from elevated T-cell and NK-cell activity justified our discovery effort toward Cbl-b inhibitors that might show therapeutic promise in immuno-oncology, where activation of the immune system can drive the recognition and killing of cancer cells.
We undertook a high-throughput screening campaign followed by structure-enabled optimization to develop a novel benzodiazepine series of potent Cbl-b inhibitors. This series displayed nanomolar levels of biochemical potency, as well as potent T-cell activation. The functional activity of this class of Cbl-b inhibitors was further corroborated with ubiquitin-based cellular assays.
论文信息
- 作者
- Boerth JA、Chinn AJ、Schimpl M、Bommakanti G、Chan C、Code EL、Giblin KA、Gohlke A
- 单位
- Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.United States
- 期刊
- ACS medicinal chemistry letters2023 Dec 14
- 原文标识
- PubMed 38116444 · DOI 10.1021/acsmedchemlett.3c00439
在 PubMed 查看 → 出版商原文（DOI） 全文 PDF（PMC）· 可下载 治疗专题与资料阅读指南 资料来源与翻译说明 报告译文或资料问题 →