Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer In Vitro and In Vivo

The estrogen receptor (ER) is a well-established target for endocrine therapies of ER-positive breast cancer (ER+ BC), but endocrine resistance limits the efficacy of clinical drugs. Using proteolysis targeting chimera (PROTAC) technology to degrade ERα may be an effective alternative to endocrine therapies. Herein, we disclose a novel series of potent and selective ERα PROTACs based on an oxabicycloheptane sulfonamide (OBHSA) scaffold, with no associated ERβ degradation. These PROTACs showed significant antiproliferation and ERα degradation activities against a broad spectrum of ER+ BC cells including tamoxifen-resistant and ERα mutant cell lines. Genomics analysis confirmed that these PROTACs inhibited the nascent RNA synthesis of ERα target genes and impaired genome-wide ERα binding. Compound ZD12 exhibited excellent antitumor potency and ERα degradation activity in both tamoxifen-sensitive and -resistant BC mice models, which are superior to fulvestrant. This study demonstrates the potential of these PROTACs as novel drug candidates for endocrine-resistant BC treatment.

雌激素受体（estrogen receptor, ER）是ER阳性乳腺癌（ER-positive breast cancer, ER+ BC）内分泌治疗的经典靶点，但内分泌耐药限制了临床药物的疗效。采用蛋白降解靶向嵌合体（proteolysis targeting chimera, PROTAC）技术降解ERα或许是内分泌治疗的有效替代方案。本文报道了一类基于氧双环庚烷磺酰胺（oxabicycloheptane sulfonamide, OBHSA）骨架的新型强效选择性ERα PROTAC，该类化合物不会诱导ERβ降解。这类PROTAC对包括他莫昔芬耐药株及ERα突变细胞系在内的多种ER+乳腺癌细胞均表现出显著的抗增殖与ERα降解活性。基因组学分析证实，此类PROTAC可抑制ERα靶基因的新生RNA合成，并损害全基因组范围内的ERα结合能力。化合物ZD12在他莫昔芬敏感及耐药乳腺癌小鼠模型中均展现出优异的抗肿瘤活性与ERα降解效果，其疗效优于氟维司群（fulvestrant）。本研究表明，此类PROTAC有望成为治疗内分泌耐药乳腺癌的新型候选药物。