Lawrence Snyder, J. Flanagan, Y. Qian, S. Gough, M. Andreoli, M. Bookbinder, G. Cadelina, J. Bradley, E. Rousseau, J. Chandler, Ryan R. Willard, J. Pizzano, C. Crews, A. Crew, J. Houston, Marcia Dougan Moore, R. Peck, I. Taylor
{"title":"摘要:口服生物可利用雌激素受体降解PROTAC的ARV-471的发现可用于治疗乳腺癌患者","authors":"Lawrence Snyder, J. Flanagan, Y. Qian, S. Gough, M. Andreoli, M. Bookbinder, G. Cadelina, J. Bradley, E. Rousseau, J. Chandler, Ryan R. Willard, J. Pizzano, C. Crews, A. Crew, J. Houston, Marcia Dougan Moore, R. Peck, I. Taylor","doi":"10.1158/1538-7445.AM2021-44","DOIUrl":null,"url":null,"abstract":"ARV-471, an estrogen receptor (ER) alpha PROTAC® protein degrader, is a hetero-bifunctional molecule that facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex, leading to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ~ 1 nM. PROTAC® mediated ER degradation decreases the expression of classically regulated ER-target genes and inhibits cell proliferation of ER-dependent cell lines (MCF7, T47D). Additionally, ARV-471 degrades clinically relevant ESR1 variants (Y537S and D538G) and inhibits growth of cell lines expressing those variants. In an immature rat uterotrophic model, ARV-471 degrades rat uterine ER and demonstrates no agonist activity. Daily, oral-administration of single agent ARV-471 (3, 10, and 30 mpk) leads to significant anti-tumor activity of estradiol-dependent MCF7 xenografts and concomitant tumor ER protein reductions of >90% at study termination. Moreover, when a CDK4/6 inhibitor is combined with ARV-471 in the MCF7 model, even more pronounced tumor growth inhibition is observed (131% TGI), accompanied by significant reductions in ER protein levels. In an ESR1 Y537S, hormone-independent patient-derived xenograft model, ARV-471 at 10 mpk completely inhibited growth and also significantly reduced mutant ER protein levels. Taken together, the preclinical data of ARV-471 supports its continued development as a best-in-class oral ER PROTAC® protein degrader. These preclinical data supported the clinical development of ARV-471 for the treatment of patients with breast cancer. The discovery, chemical structure and initial clinical data of ARV-471 will be presented. Citation Format: Lawrence B. Snyder, John J. Flanagan, Yimin Qian, Sheryl M. Gough, Monica Andreoli, Mark Bookbinder, Gregory Cadelina, John Bradley, Emma Rousseau, Julian Chandler, Ryan Willard, Jennifer Pizzano, Craig M. Crews, Andrew P. Crew, John Houston, Marcia Dougan Moore, Ron Peck, Ian Taylor. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. 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Daily, oral-administration of single agent ARV-471 (3, 10, and 30 mpk) leads to significant anti-tumor activity of estradiol-dependent MCF7 xenografts and concomitant tumor ER protein reductions of >90% at study termination. Moreover, when a CDK4/6 inhibitor is combined with ARV-471 in the MCF7 model, even more pronounced tumor growth inhibition is observed (131% TGI), accompanied by significant reductions in ER protein levels. In an ESR1 Y537S, hormone-independent patient-derived xenograft model, ARV-471 at 10 mpk completely inhibited growth and also significantly reduced mutant ER protein levels. Taken together, the preclinical data of ARV-471 supports its continued development as a best-in-class oral ER PROTAC® protein degrader. These preclinical data supported the clinical development of ARV-471 for the treatment of patients with breast cancer. The discovery, chemical structure and initial clinical data of ARV-471 will be presented. Citation Format: Lawrence B. Snyder, John J. 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引用次数: 28
摘要
ARV-471是雌激素受体(ER) α PROTAC®蛋白降解物,是一种异源双功能分子,促进雌激素受体α与细胞内E3连接酶复合物之间的相互作用,导致雌激素受体通过蛋白酶体泛素化和随后的降解。ARV-471在雌激素受体阳性的乳腺癌细胞株中对雌激素受体有较强的降解作用,一半最大降解浓度(DC50)约为1 nM。PROTAC®介导的内质网降解降低经典内质网靶基因的表达,抑制内质网依赖细胞系的细胞增殖(MCF7, T47D)。此外,ARV-471可降解临床相关的ESR1变体(Y537S和D538G),并抑制表达这些变体的细胞系的生长。在未成熟大鼠子宫萎缩模型中,ARV-471可降解大鼠子宫内质网,且无激动剂活性。每日口服单药ARV-471(3,10和30mpk)可导致雌二醇依赖性MCF7异种移植物的显著抗肿瘤活性,并在研究结束时伴随肿瘤ER蛋白降低>90%。此外,当CDK4/6抑制剂与ARV-471在MCF7模型中联合使用时,观察到更明显的肿瘤生长抑制(131% TGI),并伴有内质网蛋白水平的显著降低。在ESR1 Y537S,激素不依赖的患者来源的异种移植模型中,ARV-471在10 mpk时完全抑制生长,并显著降低突变ER蛋白水平。综上所述,ARV-471的临床前数据支持其作为同类最佳口服ER PROTAC®蛋白降解剂的持续发展。这些临床前数据支持了ARV-471用于治疗乳腺癌患者的临床开发。本文将介绍ARV-471的发现、化学结构和初步临床数据。引文格式:Lawrence B. Snyder、John J. Flanagan、钱一民、Sheryl M. Gough、Monica Andreoli、Mark Bookbinder、Gregory Cadelina、John Bradley、Emma Rousseau、Julian Chandler、Ryan Willard、Jennifer Pizzano、Craig M. Crews、Andrew P. Crew、John Houston、Marcia Dougan Moore、Ron Peck、Ian Taylor。口服生物可利用雌激素受体降解PROTAC的ARV-471的发现用于治疗乳腺癌患者[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要第44期。
Abstract 44: The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer
ARV-471, an estrogen receptor (ER) alpha PROTAC® protein degrader, is a hetero-bifunctional molecule that facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex, leading to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ~ 1 nM. PROTAC® mediated ER degradation decreases the expression of classically regulated ER-target genes and inhibits cell proliferation of ER-dependent cell lines (MCF7, T47D). Additionally, ARV-471 degrades clinically relevant ESR1 variants (Y537S and D538G) and inhibits growth of cell lines expressing those variants. In an immature rat uterotrophic model, ARV-471 degrades rat uterine ER and demonstrates no agonist activity. Daily, oral-administration of single agent ARV-471 (3, 10, and 30 mpk) leads to significant anti-tumor activity of estradiol-dependent MCF7 xenografts and concomitant tumor ER protein reductions of >90% at study termination. Moreover, when a CDK4/6 inhibitor is combined with ARV-471 in the MCF7 model, even more pronounced tumor growth inhibition is observed (131% TGI), accompanied by significant reductions in ER protein levels. In an ESR1 Y537S, hormone-independent patient-derived xenograft model, ARV-471 at 10 mpk completely inhibited growth and also significantly reduced mutant ER protein levels. Taken together, the preclinical data of ARV-471 supports its continued development as a best-in-class oral ER PROTAC® protein degrader. These preclinical data supported the clinical development of ARV-471 for the treatment of patients with breast cancer. The discovery, chemical structure and initial clinical data of ARV-471 will be presented. Citation Format: Lawrence B. Snyder, John J. Flanagan, Yimin Qian, Sheryl M. Gough, Monica Andreoli, Mark Bookbinder, Gregory Cadelina, John Bradley, Emma Rousseau, Julian Chandler, Ryan Willard, Jennifer Pizzano, Craig M. Crews, Andrew P. Crew, John Houston, Marcia Dougan Moore, Ron Peck, Ian Taylor. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 44.