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针对PCNA的新型化学支架的查确定了Hsp90alpha抑制剂SNX-211212的存在

Jennifer Jossart¹, Ning Ma², Pouya Haratipour¹

¹Department of Cancer Biology and Molecular Medicine, City of Hope Medical Center, Monrovia, CA, USA.

Current research in structural biology

|February 26, 2026

概括

研究人员发现了一种利用Hsp90α抑制剂SNX-2112.2向增殖细胞核抗原 (PCNA) 的新方法. 这一发现揭示了一个新的化学支架,用于开发用于癌症和其他疾病的新PCNA抑制剂.

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:

增殖细胞核抗原 (PCNA) 是DNA复制和修复的关键调节剂,与癌症和病毒感染有关.
由于其作为分子枢纽的复杂作用,PCNA被认为是"不可抗药的".
之前开发的一种PCNA抑制剂AOH1996正在进行1期临床试验,证明PCNA是一种可行的治疗标.

研究的目的:

与AOH1996.6.相比,识别具有更好的功效,稳定性和替代作用机制的新型PCNA抑制剂.
探索新的化学支架,以针对各种疾病中的PCNA.
为了解决对现有PCNA抑制剂的潜在耐药性.

主要方法:

利用基于人工智能的计算屏幕与热转移测试相结合.
通过蛋白质结晶学描述了一种新型的命中化合物.
采用细胞热转移测定和蛋白质丧计算用于化合物验证.

主要成果:

确定了Hsp90α抑制剂SNX-2112作为一种针对PCNA的新型打击化合物.
在主要的PIP-box结合口袋中,SNX-2112与PCNA结合.
这种结合相互作用揭示了PCNA抑制剂开发的新化学支架.

结论:

SNX-2112代表了一个有前途的新化学支架,用于开发新型PCNA抑制剂.
这一发现为改善治疗选择和克服抵抗机制提供了潜力.
这些发现扩大了可用于药物治疗的PCNA向剂的范围,用于各种疾病.

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