{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T13:40:01Z","timestamp":1784036401027,"version":"3.55.0"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T00:00:00Z","timestamp":1583280000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T00:00:00Z","timestamp":1583280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"G1 Therapeutics"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Breast Cancer Res Treat"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>The combination of targeting the CDK4\/6 and estrogen receptor (ER) signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER-positive breast cancer. However, the poor physicochemical properties of fulvestrant require monthly intramuscular injections to patients, which limit the pharmacokinetic and pharmacodynamic activity of the compound. Therefore, an orally available compound that more rapidly reaches steady state may lead to a better clinical response in patients. Here, we report the identification of G1T48, a novel orally bioavailable, non-steroidal small molecule antagonist of ER.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The pharmacological effects and the antineoplastic mechanism of action of G1T48 on tumors was evaluated using human breast cancer cells (in vitro) and xenograft efficacy models (in vivo).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>G1T48 is a potent and efficacious inhibitor of estrogen-mediated transcription and proliferation in ER-positive breast cancer cells, similar to the pure antiestrogen fulvestrant. In addition, G1T48 can effectively suppress ER activity in multiple models of endocrine therapy resistance including those harboring ER mutations and growth factor activation. In vivo, G1T48 has robust antitumor activity in a model of estrogen-dependent breast cancer (MCF7) and significantly inhibited the growth of tamoxifen-resistant (TamR), long-term estrogen-deprived (LTED) and patient-derived xenograft tumors with an increased response being observed with the combination of G1T48 and the CDK4\/6 inhibitor lerociclib.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>These data show that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER-positive breast cancer.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10549-020-05575-9","type":"journal-article","created":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T06:13:21Z","timestamp":1583302401000},"page":"635-646","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["G1T48, an oral selective estrogen receptor degrader, and the CDK4\/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer"],"prefix":"10.1007","volume":"180","author":[{"given":"Kaitlyn J.","family":"Andreano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne E.","family":"Wardell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer G.","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor K.","family":"Desautels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Baldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina A.","family":"Chao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendall A.","family":"Heetderks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeeun","family":"Bae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra A.","family":"Tonetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M.","family":"Gutgesell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica A.","family":"Sorrentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delita A.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E.","family":"Bisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay C.","family":"Strum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory R. J.","family":"Thatcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6553-8053","authenticated-orcid":false,"given":"John D.","family":"Norris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,4]]},"reference":[{"issue":"9","key":"5575_CR1","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/nrclinonc.2013.124","volume":"10","author":"M Ignatiadis","year":"2013","unstructured":"Ignatiadis M, Sotiriou C (2013) Luminal breast cancer: from biology to treatment. Nat Rev Clin Oncol 10(9):494\u2013506","journal-title":"Nat Rev Clin Oncol"},{"issue":"2","key":"5575_CR2","doi-asserted-by":"publisher","first-page":"135","DOI":"10.2174\/1574884711308020006","volume":"8","author":"PY Maximov","year":"2013","unstructured":"Maximov PY, Lee TM, Jordan VC (2013) The discovery and development of Selective Estrogen Receptor Modulators (SERMs) for clinical practice. Curr Clin Pharmacol 8(2):135\u2013155","journal-title":"Curr Clin Pharmacol"},{"key":"5575_CR3","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.breast.2016.01.006","volume":"26","author":"L Ryd\u00e9n","year":"2016","unstructured":"Ryd\u00e9n L et al (2016) Aromatase inhibitors alone or sequentially combined with tamoxifen in postmenopausal early breast cancer compared with tamoxifen or placebo - Meta-analyses on efficacy and adverse events based on randomized clinical trials. Breast 26:106\u2013114","journal-title":"Breast"},{"issue":"14","key":"5575_CR4","doi-asserted-by":"publisher","first-page":"5041","DOI":"10.1128\/MCB.20.14.5041-5047.2000","volume":"20","author":"J Font de Mora","year":"2000","unstructured":"Font de Mora J, Brown M (2000) AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. Mol Cell Biol 20(14):5041\u20135047","journal-title":"Mol Cell Biol"},{"issue":"13","key":"5575_CR5","doi-asserted-by":"publisher","first-page":"9817","DOI":"10.1074\/jbc.M010840200","volume":"276","author":"RA Campbell","year":"2001","unstructured":"Campbell RA et al (2001) Phosphatidylinositol 3-kinase\/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 276(13):9817\u20139824","journal-title":"J Biol Chem"},{"issue":"9","key":"5575_CR6","doi-asserted-by":"publisher","first-page":"3221","DOI":"10.1210\/en.2002-220186","volume":"143","author":"W Yue","year":"2002","unstructured":"Yue W et al (2002) Activation of the MAPK pathway enhances sensitivity of MCF-7 breast cancer cells to the mitogenic effect of estradiol. Endocrinology 143(9):3221\u20133229","journal-title":"Endocrinology"},{"issue":"38","key":"5575_CR7","doi-asserted-by":"publisher","first-page":"33006","DOI":"10.1074\/jbc.M506758200","volume":"280","author":"S Medunjanin","year":"2005","unstructured":"Medunjanin S et al (2005) Glycogen synthase kinase-3 interacts with and phosphorylates estrogen receptor alpha and is involved in the regulation of receptor activity. J Biol Chem 280(38):33006\u201333014","journal-title":"J Biol Chem"},{"issue":"10","key":"5575_CR8","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1038\/nrclinonc.2015.117","volume":"12","author":"R Jeselsohn","year":"2015","unstructured":"Jeselsohn R et al (2015) ESR1 mutations\u2014a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol 12(10):573\u2013583","journal-title":"Nat Rev Clin Oncol"},{"issue":"5","key":"5575_CR9","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/nrc3920","volume":"15","author":"CX Ma","year":"2015","unstructured":"Ma CX et al (2015) Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer 15(5):261\u2013275","journal-title":"Nat Rev Cancer"},{"key":"5575_CR10","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.ctrv.2016.08.008","volume":"50","author":"K Tryfonidis","year":"2016","unstructured":"Tryfonidis K et al (2016) Endocrine treatment in breast cancer: cure, resistance and beyond. Cancer Treat Rev 50:68\u201381","journal-title":"Cancer Treat Rev"},{"issue":"1","key":"5575_CR11","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s40487-017-0046-2","volume":"5","author":"MR Nathan","year":"2017","unstructured":"Nathan MR, Schmid P (2017) A review of fulvestrant in breast cancer. Oncol Ther 5(1):17\u201329","journal-title":"Oncol Ther"},{"issue":"12","key":"5575_CR12","doi-asserted-by":"publisher","first-page":"4883","DOI":"10.1021\/acs.jmedchem.5b00760","volume":"58","author":"DP McDonnell","year":"2015","unstructured":"McDonnell DP, Wardell SE, Norris JD (2015) Oral selective estrogen receptor downregulators (SERDs), a breakthrough endocrine therapy for breast cancer. J Med Chem 58(12):4883\u20134887","journal-title":"J Med Chem"},{"issue":"6","key":"5575_CR13","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1016\/S1470-2045(16)00106-6","volume":"17","author":"IE Krop","year":"2016","unstructured":"Krop IE et al (2016) Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 17(6):811\u2013821","journal-title":"Lancet Oncol"},{"issue":"7","key":"5575_CR14","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1016\/S1470-2045(17)30376-5","volume":"18","author":"J Baselga","year":"2017","unstructured":"Baselga J et al (2017) Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18(7):904\u2013916","journal-title":"Lancet Oncol"},{"key":"5575_CR15","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.ejca.2018.08.002","volume":"103","author":"M Campone","year":"2018","unstructured":"Campone M et al (2018) Buparlisib plus fulvestrant versus placebo plus fulvestrant for postmenopausal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer: overall survival results from BELLE-2. Eur J Cancer 103:147\u2013154","journal-title":"Eur J Cancer"},{"issue":"1","key":"5575_CR16","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/S1470-2045(17)30688-5","volume":"19","author":"A Di Leo","year":"2018","unstructured":"Di Leo A et al (2018) Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 19(1):87\u2013100","journal-title":"Lancet Oncol"},{"issue":"4","key":"5575_CR17","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/S1470-2045(15)00613-0","volume":"17","author":"M Cristofanilli","year":"2016","unstructured":"Cristofanilli M et al (2016) Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 17(4):425\u2013439","journal-title":"Lancet Oncol"},{"issue":"25","key":"5575_CR18","doi-asserted-by":"publisher","first-page":"2875","DOI":"10.1200\/JCO.2017.73.7585","volume":"35","author":"GW Sledge","year":"2017","unstructured":"Sledge GW et al (2017) MONARCH 2: abemaciclib in combination with fulvestrant in women With HR+\/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 35(25):2875\u20132884","journal-title":"J Clin Oncol"},{"issue":"24","key":"5575_CR19","doi-asserted-by":"publisher","first-page":"2465","DOI":"10.1200\/JCO.2018.78.9909","volume":"36","author":"DJ Slamon","year":"2018","unstructured":"Slamon DJ et al (2018) Phase III Randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 36(24):2465\u20132472","journal-title":"J Clin Oncol"},{"issue":"20","key":"5575_CR20","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1056\/NEJMoa1810527","volume":"379","author":"NC Turner","year":"2018","unstructured":"Turner NC et al (2018) Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 379(20):1926\u20131936","journal-title":"N Engl J Med"},{"issue":"4","key":"5575_CR21","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.clbc.2011.02.002","volume":"11","author":"A Howell","year":"2011","unstructured":"Howell A, Sapunar F (2011) Fulvestrant revisited: efficacy and safety of the 500-mg dose. Clin Breast Cancer 11(4):204\u2013210","journal-title":"Clin Breast Cancer"},{"issue":"8","key":"5575_CR22","doi-asserted-by":"publisher","first-page":"529","DOI":"10.2165\/00003088-200443080-00003","volume":"43","author":"JF Robertson","year":"2004","unstructured":"Robertson JF et al (2004) Pharmacokinetic profile of intramuscular fulvestrant in advanced breast cancer. Clin Pharmacokinet 43(8):529\u2013538","journal-title":"Clin Pharmacokinet"},{"issue":"6","key":"5575_CR23","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1158\/1078-0432.CCR-14-1178","volume":"21","author":"P Heidari","year":"2015","unstructured":"Heidari P et al (2015) Pharmacodynamic imaging guides dosing of a selective estrogen receptor degrader. Clin Cancer Res 21(6):1340\u20131347","journal-title":"Clin Cancer Res"},{"issue":"4","key":"5575_CR24","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1021\/acs.jmedchem.6b01355","volume":"60","author":"R Xiong","year":"2017","unstructured":"Xiong R et al (2017) Novel selective estrogen receptor downregulators (SERDs) developed against treatment-resistant breast cancer. J Med Chem 60(4):1325\u20131342","journal-title":"J Med Chem"},{"issue":"26","key":"5575_CR25","doi-asserted-by":"publisher","first-page":"42343","DOI":"10.18632\/oncotarget.16216","volume":"8","author":"JE Bisi","year":"2017","unstructured":"Bisi JE et al (2017) Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4\/6 for use as an oral antineoplastic in patients with CDK4\/6 sensitive tumors. Oncotarget 8(26):42343\u201342358","journal-title":"Oncotarget"},{"issue":"6","key":"5575_CR26","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1158\/1541-7786.MCR-17-0028","volume":"15","author":"JP Stice","year":"2017","unstructured":"Stice JP et al (2017) CDK4\/6 Therapeutic intervention and viable alternative to taxanes in CRPC. Mol Cancer Res 15(6):660\u2013669","journal-title":"Mol Cancer Res"},{"issue":"12","key":"5575_CR27","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1158\/1541-7786.MCR-14-0195","volume":"12","author":"TM Wright","year":"2014","unstructured":"Wright TM et al (2014) Delineation of a FOXA1\/ERalpha\/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer. Mol Cancer Res 12(12):1829\u20131839","journal-title":"Mol Cancer Res"},{"key":"5575_CR28","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"K Livak","year":"2001","unstructured":"Livak K, Schmittgen T (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(\u0394\u0394C(T)) method. Methods 25:402\u2013408","journal-title":"Methods"},{"issue":"12","key":"5575_CR29","doi-asserted-by":"publisher","first-page":"4888","DOI":"10.1021\/acs.jmedchem.5b00054","volume":"58","author":"A Lai","year":"2015","unstructured":"Lai A et al (2015) Identification of GDC-0810 (ARN-810), an orally bioavailable selective estrogen receptor degrader (SERD) that Demonstrates robust activity in tamoxifen-resistant breast cancer xenografts. J Med Chem 58(12):4888\u20134904","journal-title":"J Med Chem"},{"issue":"5","key":"5575_CR30","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1530\/ERC-15-0287","volume":"22","author":"SE Wardell","year":"2015","unstructured":"Wardell SE et al (2015) Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader. Endocr Relat Cancer 22(5):713\u2013724","journal-title":"Endocr Relat Cancer"},{"key":"5575_CR31","doi-asserted-by":"publisher","first-page":"e15828","DOI":"10.7554\/eLife.15828","volume":"5","author":"JD Joseph","year":"2016","unstructured":"Joseph JD et al (2016) The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. Elife 5:e15828","journal-title":"Elife"},{"issue":"11","key":"5575_CR32","doi-asserted-by":"publisher","first-page":"3307","DOI":"10.1158\/0008-5472.CAN-15-2357","volume":"76","author":"HM Weir","year":"2016","unstructured":"Weir HM et al (2016) AZD9496: An oral estrogen receptor inhibitor that blocks the growth of ER-positive and ESR1-mutant breast tumors in preclinical models. Cancer Res 76(11):3307\u20133318","journal-title":"Cancer Res"},{"issue":"16","key":"5575_CR33","doi-asserted-by":"publisher","first-page":"4793","DOI":"10.1158\/1078-0432.CCR-16-2561","volume":"23","author":"T Bihani","year":"2017","unstructured":"Bihani T et al (2017) Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has antitumor activity in multiple ER. Clin Cancer Res 23(16):4793\u20134804","journal-title":"Clin Cancer Res"},{"issue":"7","key":"5575_CR34","doi-asserted-by":"publisher","first-page":"2837","DOI":"10.1021\/acs.jmedchem.7b01682","volume":"61","author":"GS Tria","year":"2018","unstructured":"Tria GS et al (2018) Discovery of LSZ102, a potent, orally bioavailable selective estrogen receptor degrader (SERD) for the treatment of estrogen receptor positive breast cancer. J Med Chem 61(7):2837\u20132864","journal-title":"J Med Chem"},{"issue":"4","key":"5575_CR35","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1016\/j.cell.2019.06.026","volume":"178","author":"J Guan","year":"2019","unstructured":"Guan J et al (2019) Therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell 178(4):949\u2013963.e18","journal-title":"Cell"},{"issue":"1","key":"5575_CR36","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1021\/acsmedchemlett.8b00414","volume":"10","author":"M Kahraman","year":"2019","unstructured":"Kahraman M et al (2019) Maximizing ER-\u03b1 degradation maximizes activity in a tamoxifen-resistant breast cancer model: identification of GDC-0927. ACS Med Chem Lett 10(1):50\u201355","journal-title":"ACS Med Chem Lett"},{"issue":"6","key":"5575_CR37","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1002\/jbmr.5650110615","volume":"11","author":"MW Draper","year":"1996","unstructured":"Draper MW et al (1996) A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res 11(6):835\u2013842","journal-title":"J Bone Miner Res"},{"issue":"23","key":"5575_CR38","doi-asserted-by":"publisher","first-page":"2727","DOI":"10.1001\/jama.295.23.joc60074","volume":"295","author":"VG Vogel","year":"2006","unstructured":"Vogel VG et al (2006) Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295(23):2727\u20132741","journal-title":"JAMA"},{"issue":"12","key":"5575_CR39","doi-asserted-by":"publisher","first-page":"5828","DOI":"10.1210\/endo.140.12.7164","volume":"140","author":"AL Wijayaratne","year":"1999","unstructured":"Wijayaratne AL et al (1999) Comparative analyses of mechanistic differences among antiestrogens. Endocrinology 140(12):5828\u20135840","journal-title":"Endocrinology"},{"issue":"20","key":"5575_CR40","doi-asserted-by":"publisher","first-page":"8128","DOI":"10.1021\/acs.jmedchem.5b00984","volume":"58","author":"C De Savi","year":"2015","unstructured":"De Savi C et al (2015) Optimization of a novel binding motif to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (AZD9496), a potent and orally bioavailable selective estrogen receptor downregulator and antagonist. J Med Chem 58(20):8128\u20138140","journal-title":"J Med Chem"},{"key":"5575_CR41","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.steroids.2014.07.013","volume":"90","author":"SE Wardell","year":"2014","unstructured":"Wardell SE, Nelson ER, McDonnell DP (2014) From empirical to mechanism-based discovery of clinically useful Selective Estrogen Receptor Modulators (SERMs). Steroids 90:30\u201338","journal-title":"Steroids"},{"issue":"7","key":"5575_CR42","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1210\/me.2012-1031","volume":"26","author":"SE Wardell","year":"2012","unstructured":"Wardell SE, Kazmin D, McDonnell DP (2012) Research resource: transcriptional profiling in a cellular model of breast cancer reveals functional and mechanistic differences between clinically relevant SERM and between SERM\/estrogen complexes. Mol Endocrinol 26(7):1235\u20131248","journal-title":"Mol Endocrinol"},{"issue":"6","key":"5575_CR43","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.tibs.2004.04.006","volume":"29","author":"L Nagy","year":"2004","unstructured":"Nagy L, Schwabe JW (2004) Mechanism of the nuclear receptor molecular switch. Trends Biochem Sci 29(6):317\u2013324","journal-title":"Trends Biochem Sci"},{"issue":"1","key":"5575_CR44","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s13058-017-0851-4","volume":"19","author":"A Bahreini","year":"2017","unstructured":"Bahreini A et al (2017) Mutation site and context dependent effects of ESR1 mutation in genome-edited breast cancer cell models. Breast Cancer Res 19(1):60","journal-title":"Breast Cancer Res"},{"issue":"16","key":"5575_CR45","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.1038\/onc.2016.382","volume":"36","author":"A Harrod","year":"2017","unstructured":"Harrod A et al (2017) Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer. Oncogene 36(16):2286\u20132296","journal-title":"Oncogene"},{"issue":"1","key":"5575_CR46","doi-asserted-by":"publisher","first-page":"1865","DOI":"10.1038\/s41467-017-01864-y","volume":"8","author":"LA Martin","year":"2017","unstructured":"Martin LA et al (2017) Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance. Nat Commun 8(1):1865","journal-title":"Nat Commun"},{"issue":"23","key":"5575_CR47","doi-asserted-by":"publisher","first-page":"6856","DOI":"10.1158\/0008-5472.CAN-13-1197","volume":"73","author":"K Merenbakh-Lamin","year":"2013","unstructured":"Merenbakh-Lamin K et al (2013) D538G mutation in estrogen receptor-\u03b1: A novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res 73(23):6856\u20136864","journal-title":"Cancer Res"},{"issue":"12","key":"5575_CR48","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.1038\/ng.2823","volume":"45","author":"DR Robinson","year":"2013","unstructured":"Robinson DR et al (2013) Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 45(12):1446\u20131451","journal-title":"Nat Genet"},{"issue":"12","key":"5575_CR49","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1038\/ng.2822","volume":"45","author":"W Toy","year":"2013","unstructured":"Toy W et al (2013) ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 45(12):1439\u20131445","journal-title":"Nat Genet"},{"issue":"3","key":"5575_CR50","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1158\/2159-8290.CD-15-1523","volume":"7","author":"W Toy","year":"2017","unstructured":"Toy W et al (2017) Activating ESR1 Mutations Differentially Impact the Efficacy of ER Antagonists. Cancer Discov 7(3):277\u2013287","journal-title":"Cancer Discov"},{"issue":"7","key":"5575_CR51","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1158\/1078-0432.CCR-13-2332","volume":"20","author":"R Jeselsohn","year":"2014","unstructured":"Jeselsohn R et al (2014) Emergence of constitutively active estrogen receptor-\u03b1 mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 20(7):1757\u20131767","journal-title":"Clin Cancer Res"},{"issue":"22","key":"5575_CR52","doi-asserted-by":"publisher","first-page":"5121","DOI":"10.1158\/1078-0432.CCR-15-0360","volume":"21","author":"SE Wardell","year":"2015","unstructured":"Wardell SE et al (2015) Efficacy of SERD\/SERM hybrid-CDK4\/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer. Clin Cancer Res 21(22):5121\u20135130","journal-title":"Clin Cancer Res"},{"issue":"1","key":"5575_CR53","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/s10549-019-05454-y","volume":"179","author":"SE Wardell","year":"2019","unstructured":"Wardell SE et al (2019) Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-alpha degrader activity in antitumor efficacy. Breast Cancer Res Treat 179(1):67\u201377","journal-title":"Breast Cancer Res Treat"},{"issue":"30","key":"5575_CR54","doi-asserted-by":"publisher","first-page":"4594","DOI":"10.1200\/JCO.2010.28.8415","volume":"28","author":"A Di Leo","year":"2010","unstructured":"Di Leo A et al (2010) Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol 28(30):4594\u20134600","journal-title":"J Clin Oncol"},{"key":"5575_CR55","unstructured":"Di Leo A et al. (2014) Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst 106(1):djt337."},{"issue":"15","key":"5575_CR56","doi-asserted-by":"publisher","first-page":"3510","DOI":"10.1158\/1078-0432.CCR-17-3102","volume":"24","author":"EP Hamilton","year":"2018","unstructured":"Hamilton EP et al (2018) A first-in-human study of the new oral selective estrogen receptor degrader AZD9496 for ER. Clin Cancer Res 24(15):3510\u20133518","journal-title":"Clin Cancer Res"},{"issue":"9","key":"5575_CR57","doi-asserted-by":"publisher","first-page":"3901","DOI":"10.1210\/endo.138.9.5358","volume":"138","author":"TM Willson","year":"1997","unstructured":"Willson TM et al (1997) Dissection of the molecular mechanism of action of GW5638, a novel estrogen receptor ligand, provides insights into the role of estrogen receptor in bone. Endocrinology 138(9):3901\u20133911","journal-title":"Endocrinology"},{"issue":"9","key":"5575_CR58","doi-asserted-by":"publisher","first-page":"2420","DOI":"10.1158\/1078-0432.CCR-12-3771","volume":"19","author":"SE Wardell","year":"2013","unstructured":"Wardell SE et al (2013) Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease. Clin Cancer Res 19(9):2420\u20132431","journal-title":"Clin Cancer Res"},{"key":"5575_CR59","doi-asserted-by":"crossref","unstructured":"Dees EC et al (2019) First-in-human dose-escalation study of g1t48, an oral selective estrogen receptor degrader (SERD), in postmenopausal women with ER+\/Her2\u2212 locally advanced or metastatic breast cancer (ABC). European Society for Medical Oncology (ESMO), Barcelona, Spain","DOI":"10.1093\/annonc\/mdz242.035"},{"issue":"9","key":"5575_CR60","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1124\/dmd.119.087924","volume":"47","author":"KWK Cheung","year":"2019","unstructured":"Cheung KWK et al (2019) GDC-0810 Pharmacokinetics and transporter-mediated drug interaction evaluation with an endogenous biomarker in the first-in-human, dose escalation study. Drug Metab Dispos 47(9):966\u2013973","journal-title":"Drug Metab Dispos"},{"issue":"13","key":"5575_CR61","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1056\/NEJM199203263261302","volume":"326","author":"RR Love","year":"1992","unstructured":"Love RR et al (1992) Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326(13):852\u2013856","journal-title":"N Engl J Med"},{"issue":"11","key":"5575_CR62","doi-asserted-by":"publisher","first-page":"860","DOI":"10.7326\/0003-4819-115-11-860","volume":"115","author":"RR Love","year":"1991","unstructured":"Love RR et al (1991) Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 115(11):860\u2013864","journal-title":"Ann Intern Med"}],"container-title":["Breast Cancer Research and Treatment"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10549-020-05575-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s10549-020-05575-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s10549-020-05575-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:56:32Z","timestamp":1614819392000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s10549-020-05575-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,4]]},"references-count":62,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["5575"],"URL":"https:\/\/doi.org\/10.1007\/s10549-020-05575-9","relation":{},"ISSN":["0167-6806","1573-7217"],"issn-type":[{"value":"0167-6806","type":"print"},{"value":"1573-7217","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,4]]},"assertion":[{"value":"25 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"Jessica A. Sorrentino, Delita A. Thompson, John E. Bisi, and Jay C. Strum are employees of G1 Therapeutics, Inc. Delita A. Thompson, John E. Bisi, Jessica A. Sorrentino,\u00a0and Jay C. Strum own stock in G1 Therapeutics, Inc. John D. Norris is a paid consultant for G1 Therapeutics, Inc. All other authors have no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"This article does not contain any studies with human participants performed by any of the authors. All procedures were approved by the Duke University Institutional Animal Care and Use Committee (IACUC) prior to initiating the experiment (protocol A011-16-01 and A272-18-12).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}