选择性化疗的背景下，针对转录-复制冲突的小分子靶向治疗
Small molecule targeting of transcription-replication conflict for selective chemotherapy.
发表日期：2023 Jul 26
作者：
Long Gu, Min Li, Caroline M Li, Pouya Haratipour, Robert Lingeman, Jennifer Jossart, Margarita Gutova, Linda Flores, Caitlyn Hyde, Nikola Kenjić, Haiqing Li, Vincent Chung, Hongzhi Li, Brett Lomenick, Daniel D Von Hoff, Timothy W Synold, Karen S Aboody, Yilun Liu, David Horne, Robert J Hickey, J Jefferson P Perry, Linda H Malkas
来源：
Epigenetics & Chromatin
摘要：
靶向转录复制冲突可能成为内源性DNA双链断裂和基因组不稳定的重要来源，对抗癌症具有重要的治疗意义。细胞核增生相关抗原（PCNA）对DNA复制和修复过程至关重要。通过合理的药物设计方法，我们发现了一种小分子PCNA抑制剂AOH1996，它选择性地杀死癌细胞。AOH1996增强PCNA与RNA聚合酶II最大亚基RPB1之间的相互作用，解离PCNA与活跃转录的染色质区域的结合，同时以转录依赖的方式诱导DNA双链断裂。RPB1在PCNA结合区域的一点突变削弱了与PCNA的相互作用，并使癌细胞对AOH1996产生耐药性。作为可以口服和代谢稳定的药物，AOH1996作为单药治疗或联合治疗能够抑制肿瘤生长，但没有可辨别的副作用。转录复制冲突解决的抑制剂可能为开发这种癌症选择性易感性提供新的独特治疗途径。版权所有©2023作者。由Elsevier Ltd.出版，保留所有权利。
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.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.