Wang Yubo, Xie Baohua, Deng Xiaofei, Dong Chune, Zhou Hai-Bing
Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
Frontier Science Center for Immunology and Metabolism, State Key Laboratory of Virology and Biosafety, Provincial Key Laboratory of Developmentally Originated Disease, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE), Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University, Wuhan 430071, China.
J Med Chem. 2025 Jul 10;68(13):13640-13660. doi: 10.1021/acs.jmedchem.5c00495. Epub 2025 Jun 17.
Inhibiting the estrogen receptor α (ERα) signaling axis constitutes a fundamental approach in therapy for ERα-positive breast cancer (ERα BC). However, the emergence of intrinsic and acquired resistance to endocrine therapies poses a significant challenge. Alternatively, targeting the coactivator binding site (CBS) of ERα instead of the conventional ligand binding domain (LBD) may directly disrupt the ERα transcription process, thereby circumventing resistance associated with LBD mutations. Herein, we report the development of first-in-class PROTACs targeting the unconventional coactivator binding site (CBS) of ERα. Among them, displayed potent and selective ERα degradation and antiproliferative effects in multiple BC cell lines with wild-type or mutant ERα. , exhibited excellent antitumor and ERα degradation activity in MCF-7 and drug-resistant LCC-2 xenografted models. These findings demonstrated that may offer a novel degradation strategy to overcome endocrine resistance, providing new opportunities for the development of innovative treatments for ERα BC.
抑制雌激素受体α（ERα）信号轴是ERα阳性乳腺癌（ERα BC）治疗的基本方法。然而，对内分泌治疗的内在和获得性耐药的出现构成了重大挑战。另外，靶向ERα的共激活因子结合位点（CBS）而非传统的配体结合域（LBD）可能直接破坏ERα转录过程，从而规避与LBD突变相关的耐药性。在此，我们报告了靶向ERα非常规共激活因子结合位点（CBS）的一流PROTAC的开发。其中， 在多种具有野生型或突变型ERα的BC细胞系中表现出强效且选择性的ERα降解和抗增殖作用。 在MCF-7和耐药LCC-2异种移植模型中表现出优异的抗肿瘤和ERα降解活性。这些发现表明， 可能提供一种克服内分泌耐药的新型降解策略，为ERα BC创新治疗的开发提供新机会。
