H3 Biomedicine, Inc., Cambridge, Massachusetts.
Eisai Inc., Andover, Massachusetts.
Cancer Res. 2019 Apr 15;79(8):1740-1745. doi: 10.1158/0008-5472.CAN-18-3634. Epub 2019 Apr 5.
The development of tamoxifen and subsequent estrogen receptor alpha (ERα) antagonists represents a tremendous therapeutic breakthrough in the treatment of breast cancer. Despite the ability of ERα antagonists to increase survival rates, resistance to these therapies is an all-too-common occurrence. The majority of resistant tumors, including those with hotspot mutations in the ligand-binding domain of ERα, remain dependent on ERα signaling, indicating that either a more potent or novel class of antagonist could have clinical benefit. With this thought in mind, we developed a novel ERα antagonist that exhibits enhanced potency due to its ability to covalently target a unique cysteine in ER. This review describes the design of this antagonist, H3B-5942, and discusses opportunities for future improvements, which could reduce the risk of escape mutations to this therapeutic modality.
他莫昔芬和随后的雌激素受体α（ERα）拮抗剂的发展代表了乳腺癌治疗中的一个巨大的治疗突破。尽管 ERα 拮抗剂能够提高生存率，但对这些治疗的耐药性是很常见的。大多数耐药肿瘤，包括 ERα 配体结合域热点突变的肿瘤，仍然依赖于 ERα 信号，这表明更有效的或新型的拮抗剂可能具有临床获益。考虑到这一点，我们开发了一种新型的 ERα 拮抗剂，由于其能够共价靶向 ER 中的独特半胱氨酸，因此具有增强的效力。本文描述了这种拮抗剂 H3B-5942 的设计，并讨论了未来改进的机会，这可能会降低这种治疗方式发生逃逸突变的风险。
