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徐炳祥
(2023-08-14 21:58):
#paper doi: 10.1016/j.chembiol.2023.07.001 Cell Chemical Biology, 2023, Small molecule targeting of transcription-replication conflict for selective chemotherapy。本文是最近肿瘤治化疗领域内的一项重要新闻，作者在之前研究的基础上设计了一种新的小分子药物AOH1996，该药物通过增强PCNA与RPB1的结合从而将PCNA带离染色质，进而引起伴随转录的DNA复制抑制和不能被修复的DNA双链断裂损伤。通过此机制，AOH1996实现了对癌细胞的特异性杀灭，而对正常细胞几乎无毒性。动物实验和细胞实验均证明单独使用AOH1996或与其他药物联合对大部分实体肿瘤均有或多或少的疗效。本文再一次展现了针对DNA损伤修复机制的抗肿瘤药物设计的潜力。
Abstract:
Targeting transcription replication conflicts, a major source of endogenous DNA double-stranded breaks and genomic instability could have important anticancer therapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNA …
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Targeting transcription replication conflicts, a major source of endogenous DNA double-stranded breaks and genomic instability could have important anticancer therapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNA replication and repair processes. Through a rational drug design approach, we identified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells. AOH1996 enhances the interaction between PCNA and the largest subunit of RNA polymerase II, RPB1, and dissociates PCNA from actively transcribed chromatin regions, while inducing DNA double-stranded breaks in a transcription-dependent manner. Attenuation of RPB1 interaction with PCNA, by a point mutation in RPB1's PCNA-binding region, confers resistance to AOH1996. Orally administrable and metabolically stable, AOH1996 suppresses tumor growth as a monotherapy or as a combination treatment but causes no discernable side effects. Inhibitors of transcription replication conflict resolution may provide a new and unique therapeutic avenue for exploiting this cancer-selective vulnerability.
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