攻克癌症不是梦       抗癌药AOH 1996  可治愈各种实体瘤。     

选择性化疗中转录-复制冲突的小分子靶向作用

https://pubmed.ncbi.nlm.nih.gov/37531956/

        靶向转录复制冲突、内源性DNA双链断裂和基因组不稳定性的主要来源可能具有重要的抗癌治疗意义。

增殖细胞核抗原（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，我们鉴定了

一种小分子PCNA抑制剂AOH1996，它选择性地杀死癌症细胞。AOH1996增强了PCNA与RNA聚合

酶II最大亚基RPB1之间的相互作用，并将PCNA从主动转录的染色质区域解离，同时以转录依赖的方式

诱导DNA双链断裂。通过RPB1的PCNA结合区的点突变减弱RPB1与PCNA的相互作用，赋予对

AOH1996的抗性。AOH1996口服且代谢稳定，可作为单一疗法或联合疗法抑制肿瘤生长，但不会

产生明显的副作用。转录-复制冲突抑制剂。

http://www.pubmedplus.cn/P/SearchQuickResult?wd=8d31c992-bcf3-4a7e-8067-eb693397c88d

• 1. The potential of PCNA inhibition as a therapeutic strategy in cervical cancer.

  
  

  Sebastian O Wendel,Jazmine A Snow,Long Gu,Nilam Sanjib Banerjee,Linda Malkas,Nicholas A Wallace

  Division of Biology, Kansas State University, Manhattan, Kansas, USA.

  
  

  J Med Virol (P 1096-9071 E 0146-6615) 2023 年 95 卷 11 期 e29244 页

  PMID：38010649 相似文献

  文摘 DOI链接

• 
  

  2. Small molecule targeting of transcription-replication conflict for selective chemotherapy.

  
  

  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

  Department of Molecular Diagnostics & Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA. Electronic address: Lgu@coh.org.

  Lgu@coh.org

  Cell Chem Biol (P 2451-9448 E 2451-9448) H指数：166 2023 年 30 卷 10 期 1235-1247.e6 页

  PMID：37531956 相似文献

  文摘 DOI链接 Elsevier Science

https://pubmed.ncbi.nlm.nih.gov/38010649/

Abstract

Cervical cancers are the fourth most common and most deadly cancer in women worldwide. Despite being a tremendous public health burden, few novel approaches to improve care for these malignancies have been introduced. We discuss the potential for proliferating cell nuclear antigen (PCNA) inhibition to address this need as well as the advantages and disadvantages for compounds that can therapeutically inhibit PCNA with a specific focus on cervical cancer.

Keywords: chemotherapy; disease control; human papillomavirus; oncogenesis; virus classification.

© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Statement: The authors declare the following competing financial interest(s): City of Hope’s Office of Technology Licensing has been awarded a patent on AOH1996 and its analogs. L.H. Malkas, R.J. Hickey, D. Horne, and L. Gu are listed as inventors. Received: May 12, 2022; Revised: February 12, 2023; Accepted: July 10, 2023; Published: August 1, 2023.

References

1. 
   

1. Van Doorslaer K, Li Z, Xirasagar S, et al. The Papillomavirus Episteme: a major update to the papillomavirus sequence database. Nucleic Acids Res. 2017;45(Database issue):D499–D506. doi:10.1093/nar/gkw879 - DOI - PMC - PubMed

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1. WHO | Human papillomavirus (HPV) and cervical cancer. WHO. Published November 18, 2016. Accessed November 18, 2016. http://www.who.int/mediacentre/factsheets/fs380/en/

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1. Carter JR, Ding Z, Rose BR. HPV infection and cervical disease: A review. Australian and New Zealand Journal of Obstetrics and Gynaecology. 2011;51(2):103–108. doi:10.1111/j.1479-828X.2010.01269.x - DOI - PubMed

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1. Berman TA, Schiller JT. Human papillomavirus in cervical cancer and oropharyngeal cancer: One cause, two diseases. Cancer. 2017;123(12):2219–2229. doi:10.1002/cncr.30588 - DOI - PubMed

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1. Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. The Lancet. 2019;393(10167):169–182. doi:10.1016/S0140-6736(18)32470-X - DOI - PubMed

Show all 81 references

Publication types

• Review

• Research Support, N.I.H., Extramural

MeSH terms

• Female

• Humans

• Proliferating Cell Nuclear Antigen

• Uterine Cervical Neoplasms* / drug therapy

• Uterine Cervical Neoplasms* / pathology

Substances

• Proliferating Cell Nuclear Antigen

Related information

• MedGen

Grants and funding

• R21 AI173784/AI/NIAID NIH HHS/United States

• P20 GM103418/GM/NIGMS NIH HHS/United States

• P20 GM130448/GM/NIGMS NIH HHS/United States

• P20GM130448/NH/NIH HHS/United States

• R21 CA216789/CA/NCI NIH HHS/United States

Show all 7 grants

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• Medical

• Genetic Alliance

• International Agency for Research on Cancer - Screening Group

• MedlinePlus Consumer Health Information

• MedlinePlus Health Information

• Miscellaneous

• NCI CPTAC Assay Portal

https://pubmed.ncbi.nlm.nih.gov/37531956/

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 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.

Keywords: DNA repair; DNA replication stress; PCNA; transcription-replication conflict.

Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare the following competing financial interest(s): City of Hope’s Office of Technology Licensing has been awarded a patent on AOH1996 and its analogs. L.H. Malkas, R.J. Hickey, D. Horne, and L. Gu are listed as inventors.

Figures

Figure 1.. AOH1160 analog interactions with PCNA

Figure 2.. Interaction of AOH1996 with PCNA

Figure 3.. Therapeutic properties of AOH1996 

(A)…

Figure 4.. Pharmacokinetics and anti-tumor growth activity…

Figure 5.. Modulation of PCNA interaction with…

Figure 6.. The effect of AOH1996 is…

All figures (7)

Cited by

• The potential of PCNA inhibition as a therapeutic strategy in cervical cancer.

  Wendel SO, Snow JA, Gu L, Banerjee NS, Malkas L, Wallace NA.J Med Virol. 2023 Nov;95(11):e29244. doi: 10.1002/jmv.29244.PMID: 38010649 Review.

References

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1. Krishna TS, Kong XP, Gary S, Burgers PM, and Kuriyan J. (1994). Crystal structure of the eukaryotic DNA polymerase processivity factor PCNA. Cell 79, 1233–1243. - PubMed

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1. Tsutakawa SE, Van Wynsberghe AW, Freudenthal BD, Weinacht CP, Gakhar L, Washington MT, Zhuang Z, Tainer JA, and Ivanov I. (2011). Solution X-ray scattering combined with computational modeling reveals multiple conformations of covalently bound ubiquitin on PCNA. Proc. Natl. Acad. Sci. USA 108, 17672–17677. - PMC - PubMed

3. 
   

1. Tsutakawa SE, Yan C, Xu X, Weinacht CP, Freudenthal BD, Yang K, Zhuang Z, Washington MT, Tainer JA, and Ivanov I. (2015). Structurally distinct ubiquitin- and sumo-modified PCNA: implications for their distinct roles in the DNA damage response. Structure 23, 724–733. - PMC - PubMed

4. 
   

1. Chapados BR, Hosfield DJ, Han S, Qiu J, Yelent B, Shen B, and Tainer JA (2004). Structural basis for FEN-1 substrate specificity and PCNA-mediated activation in DNA replication and repair. Cell 116, 39–50. - PubMed

5. 
   

1. Sebesta M, Cooper CDO, Ariza A, Carnie CJ, and Ahel D. (2017). Structural insights into the function of ZRANB3 in replication stress response. Nat. Commun 8, 15847. - PMC - PubMed

Show all 63 references

Publication types

• Research Support, N.I.H., Extramural

• Research Support, U.S. Gov't, Non-P.H.S.

• Research Support, Non-U.S. Gov't

MeSH terms

• Chromatin*

• DNA

• DNA Replication

• Humans

• Neoplasms* / drug therapy

• Proliferating Cell Nuclear Antigen / chemistry

• Proliferating Cell Nuclear Antigen / genetics

• Proliferating Cell Nuclear Antigen / metabolism

• Protein Binding

Substances

• Proliferating Cell Nuclear Antigen

• Chromatin

• DNA

Related information

• MedGen

• Protein

• PubChem Compound (MeSH Keyword)

• Structure

Grants and funding

• P30 CA033572/CA/NCI NIH HHS/United States

• R01 CA121289/CA/NCI NIH HHS/United States

• R01 CA225843/CA/NCI NIH HHS/United States

LinkOut - more resources

• Full Text Sources

• Elsevier Science

• Europe PubMed Central

• PubMed Central

• Medical

• MedlinePlus Health Information

• Miscellaneous

• NCI CPTAC Assay Portal

https://kns.cnki.net/kns8s/search?classid=WD0FTY92&kw=PCNA&korder=SU

•  增殖细胞核抗原 (1346)

•  细胞增殖 (922)

•  临床意义 (687)

•  p53 (596)

•  细胞凋亡 (434)

•  乳腺癌 (363)

•  机制研究 (336)

•  相关性研究 (324)

•  P53 (316)

•  抑制作用 (272)

•  DNA (225)

•  基因表达 (224)

•  胶质瘤 (214)

•  信号通路 (202)

•  血管平滑肌细胞 (190)

•  Bcl-2 (186)

•  平滑肌细胞增殖 (174)

•  宫颈癌 (170)

•  肝再生 (168)

•  内膜增生 (165)

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