USP7 V517F突变作为抑制剂耐药性的机制
Yu-Ling Miao1, Fengying Fan2,3, Yong-Jun Cheng1
1State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
通过改变药物结合部位,USP7中的特定突变 (V517F) 会导致对USP7抑制剂的耐药性. 了解这种机制对于开发新的癌症疗法至关重要.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 开发向癌症疗法需要预测和克服耐药性.
- 美国P7抑制剂代表了一类有前途的瘤药物,但耐药性机制需要阐明.
研究的目的:
- 积极识别对USP7抑制剂的抵抗机制.
- 描述对USP7抑制剂产生抗性的突变的结构和功能影响.
主要方法:
- 利用结构分析和AlphaFold2预测来研究USP7突变.
- 采用生物化学测试来评估USP7变体和抑制剂之间的结合亲和力.
- 产生并测试了含有特定USP7突变的工程细胞系.
主要成果:
- 鉴定了USP7中出现的治疗异构基因突变V517F,作为对USP7-797.7产生抗性的主要原因.
- 结构分析显示V517F改变了结合口袋形状,导致固体阻碍和抑制剂亲和力降低.
- 具有V517F突变的工程细胞系对USP7抑制表现出显著的抵抗力,而较小的替代物显示出最小的影响.
结论:
- 在USP7中的V517F突变通过结合口袋中的固体阻碍对USP7抑制剂产生抗性.
- 这些发现支持患者分层策略和下一代USP7抑制剂的开发,以克服抗性突变.
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