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SP-1-303 is described as a potent dual-targeting small molecule identified through rational drug design, acting as a class I isoform-selective histone deacetylase inhibitor and an ATM activator. In vitro assays show selective HDAC1/HDAC3 inhibition; cellular studies report stronger growth inhibition in ER-positive breast cancer cells than in triple-negative cells and normal breast epithelium.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/dual-targeting-class-i-hdac-inhibitor-and-atm-activator-sp-1-303-preferentially-inhibits-estrogen-receptor-positive-breast-cancer-cell-growth/332238/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/dual-targeting-class-i-hdac-inhibitor-and-atm-activator-sp-1-303-preferentially-inhibits-estrogen-receptor-positive-breast-cancer-cell-growth/332238.png","ImageObject",300,407,{"name":92,"@type":93},"Aria","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What does SP-1-303 target in the study?","Question",{"text":113,"@type":114},"SP-1-303 is reported to act both as a class I HDAC inhibitor (selective for HDAC1 and HDAC3) and as an ATM activator involved in DNA damage repair signaling.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does SP-1-303 affect estrogen receptor positive breast cancer cells?",{"text":118,"@type":114},"The document reports that SP-1-303 differentially inhibits growth of ER-positive breast cancer cells (MCF-7 and T47D) and reduces estrogen receptor alpha (ER-α) expression while increasing p53 protein expression.",{"name":120,"@type":111,"acceptedAnswer":121},"What evidence supports ATM activation by SP-1-303?",{"text":122,"@type":114},"Western analysis described in the abstract shows time-dependent phosphorylation of ATM and its substrates BRCA1 and p53 in ER+ breast cancer cells after treatment.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},332238,1790197931,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":140,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":141,"language":142,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":143,"faqs":144,"seo_title":145,"seo_description":67,"update_tm":146,"read_time":147,"preview_page_count":4},2336464648322,"https://ap-avatar.wpscdn.com/avatar/2200025388227c56fec?_k=1778556882303663488","PLOS ONE  \nOPEN ACCESS  \nCitation: Jung M, Nicholas N, Grindrod S, Dritschilo A (2024) Dual-targeting class I HDAC inhibitor and ATM activator, SP-1-303, preferentially inhibits estrogen receptor positive breast cancer cell growth. PLoS ONE 19(7):  \ne0306168 . [https://doi.org/10.1371/journal](https://doi.org/10.1371/journal). pone.0306168  \nEditor: A. Ganesan, University of East Anglia, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND  \nReceived: March 20, 2024  \nAccepted: June 12, 2024  \nPublished: July 15, 2024  \nCopyright: © 2024 Jung et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.  \nData Availability Statement: All relevant data are within the manuscript.  \nFunding: This study was financially supported by the Lombardi Comprehensive Cancer Center in the form of an NIH grant (P30 CA051008) for Core facilities, including Flow Cytometry/Cell Sorting Shared Resource Lab, Tissue Culture Shared Resource Lab, and the Office of Environmental Health and Safety Georgetown University. No  \nRESEARCH ARTICLE  \nDual-targeting class I HDAC inhibitor and ATM activator, SP-1-303, preferentially inhibits estrogen receptor positive breast cancer cell growth  \nMira Jung1 *, Nicole Nicholas2, Scott Grindrod3, Anatoly Dritschilo1,3  \n1 Department of Radiation Medicine, Georgetown University School of Medicine, Washington, DC, United States of America, 2 Department of Biochemistry & Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC, United States of America, 3 Shuttle Pharmaceuticals, Inc. , Rockville, Maryland, United States of America  \n* [jungm@georgetown.edu](jungm@georgetown.edu)  \nAbstract  \nDual-targeting chromatin regulation and DNA damage repair signaling presents a promising avenue for cancer therapy. Applying rational drug design, we synthesized a potent dual-targeting small molecule, SP-1-303 . Here, we report SP-1-303 as a class I isoform selective histone deacetylase (HDAC) inhibitor and an activator of the ataxia-telangiectasia mutated protein (ATM) . In vitro enzymatic assays demonstrated selective inhibition of HDAC1 and HDAC3 . Cellular growth inhibition studies show that SP-1-303 differentially inhibits growth of estrogen receptor positive breast cancer (ER+ BC) cells with effective growth inhibition concentrations (EC50) for MCF-7 and T47D cells ranging from 0.32 to 0.34 μM, compared to 1.2–2.5 μM for triple negative breast cancer cells, and ~12 μM for normal breast epithelial cells. Western analysis reveals that SP-1-303 decreases estrogen receptor alpha (ER-α) expression and increases p53 protein expression, while inducing the phosphorylation of ATM and its substrates, BRCA1 and p53, in a time-dependent manner in ER+ BC cells. Pharmacokinetic evaluation demonstrates an area under the curve (AUC) of 5227.55 ng/ml × h with an elimination half-life of 1.26 h following intravenous administration in a rat model. Collectively, SP-1-303 emerges as a novel second generation class I (HDAC1 and HDAC3) selective HDAC inhibitor, and ATM activator, capable of modulating ER expression, and inhibiting growth of ER+ BC cells. Combined targeting of class I HDACs and ATM by SP-1- 303 offers a promising therapeutic approach for treating ER+ breast cancers and supports further preclinical evaluation.  \nIntroduction  \nBreast cancer is the most common cancer in women. Risk factors include mutations in tumor suppressor genes as well as environmental exposures. Based on U.S. Breast Cancer Statistics, about 12% of women will develop invasive breast cancer over the course of their lifetime [ 1] .  \nadditional external funding was received for this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.  \nCompeting interests: The authors have d","cbCaiapswwFcI76O","https://ap.wps.com/l/cbCaiapswwFcI76O","pdf",1863164,13,17,"English","# Abstract\n# Introduction","[{\"question\":\"What does SP-1-303 target in the study?\",\"answer\":\"SP-1-303 is reported to act both as a class I HDAC inhibitor (selective for HDAC1 and HDAC3) and as an ATM activator involved in DNA damage repair signaling.\"},{\"question\":\"How does SP-1-303 affect estrogen receptor positive breast cancer cells?\",\"answer\":\"The document reports that SP-1-303 differentially inhibits growth of ER-positive breast cancer cells (MCF-7 and T47D) and reduces estrogen receptor alpha (ER-α) expression while increasing p53 protein expression.\"},{\"question\":\"What evidence supports ATM activation by SP-1-303?\",\"answer\":\"Western analysis described in the abstract shows time-dependent phosphorylation of ATM and its substrates BRCA1 and p53 in ER+ breast cancer cells after treatment.\"}]","Dual-targeting class I HDAC inhibitor and ATM activator, SP-1-303, preferentially inhibits estrogen receptor positive breast cancer cell growth | PDF",1789997477,43]