Acquired resistance to fulvestrant and palbociclib is a new challenge to treatment of estrogen receptor positive (ER+) breast cancer. ER is expressed in most resistance settings; thus, bromodomain and extra-terminal protein inhibitors (BETi) that target BET-amplified ER-mediated transcription have therapeutic potential. Novel pyrrolopyridone BETi leveraged novel interactions with L92/L94 confirmed by a cocrystal structure of 27 with BRD4. Optimization of BETi using growth inhibition in fulvestrant-resistant (MCF-7:CFR) cells was confirmed in endocrine-resistant, palbociclib-resistant, and ESR1 mutant cell lines. 27 was more potent in MCF-7:CFR cells than six BET inhibitors in clinical trials. Transcriptomic analysis differentiated 27 from the benchmark BETi, JQ-1, showing downregulation of oncogenes and upregulation of tumor suppressors and apoptosis. The therapeutic approach was validated by oral administration of 27 in orthotopic xenografts of endocrine-resistant breast cancer in monotherapy and in combination with fulvestrant. Importantly, at an equivalent dose in rats, thrombocytopenia was mitigated.

中文翻译：

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新型吡咯并吡啶酮溴结构域和末端基序（BET）抑制剂对内分泌抗性ER +乳腺癌有效，对氟维西坦和Palbociclib具有耐药性。

对氟维司群和palbociclib的获得性耐药是治疗雌激素受体阳性（ER +）乳腺癌的新挑战。ER以大多数电阻设置表示；因此，靶向BET扩增的ER介导的转录的溴结构域和末端外蛋白抑制剂（BETi）具有治疗潜力。新型吡咯并吡啶酮BETi利用与L92 / L94的新型相互作用，该相互作用通过与BRD4的共晶结构确定为27。在耐内分泌剂，耐palbociclib和ESR1突变的细胞系中证实了在抗氟司韦特（MCF-7：CFR）细胞中使用生长抑制来优化BETi 。在临床试验中，27种在MCF-7：CFR细胞中比六种BET抑制剂更有效。转录组学分析与众不同27来自基准BETi JQ-1的数据显示癌基因的下调，肿瘤抑制因子和细胞凋亡的上调。通过单药治疗和氟维司群联合口服治疗内分泌抗性乳腺癌的原位异种移植物中的27种药物，验证了该治疗方法的有效性。重要的是，在大鼠中当量剂量下，血小板减少症得到缓解。