Development of a Precision Drug to target Y537S Mutant Estrogen Receptor in Metastatic Breast Cancer

摘要 乳腺癌是美国最常见的癌症，也是第二大死亡原因 妇女大多数乳腺癌（~75%）表达雌激素受体α（ERα）蛋白，因此 通过内分泌疗法抑制这种蛋白质功能是ER阳性乳腺癌治疗的主要手段 患者尽管如此，在接受内分泌治疗的妇女中， 与患者生存率差相关的治疗。具体而言，在许多情况下， 用内分泌疗法治疗产生了抗性肿瘤细胞的发展， 复发，表现为转移性疾病，极难控制。最近，深层DNA 测序已经在一个大的患者亚组中鉴定出ERα基因（ESR 1）特定位点的体细胞突变 乳腺癌已经扩散具体而言，Y 537 S和D538 G突变使ERα对电流产生抗性， 因此，重要的是开发一种新的靶向治疗来解决这些临床问题。 通过使用下一代ERα拮抗剂抑制ERα突变蛋白的挑战。我们的长期目标是 开发更有效和更安全的小分子药物，阻断组成型活性突变ER，用于治疗 内分泌抗性转移性乳腺癌，并有可能显着改善目前的治疗 瞄准战略。这项R21应用的短期目标是识别和开发特异性药物样 通过使用DNA编码的化学物质， 库（DEL）筛选平台。本提案的目标将通过解决以下问题进行评估 具体目标：1.我们将进行DNA编码的化学文库筛选，以鉴定小分子结合剂， 突变型ERα蛋白的配体结合结构域。2.我们将使用以下方法验证和优先考虑先导化合物： 生物化学和功能研究。我们的中心假设是高亲和力的小分子抗雌激素 对ERα突变体的特异性可抑制乳腺癌中ERα突变体的功能。这项研究将奠定 为今后的应用进行更详细的后续研究奠定基础。在成功执行此提议后， 研究计划，我们希望已经确定了突变雌激素受体的先导化合物，并可用于未来的前， 临床和临床研究。

ABSTRACT Breast cancer is the most frequently diagnosed cancer and the second leading cause of death in American women. The majority of breast cancer (~75%) expresses estrogen receptor α (ERα) protein and therefore inhibition of this protein function by endocrine therapy is the mainstay of treatment in ER-positive breast cancer patients. Nevertheless, acquired resistance has developed in nearly half of women treated with endocrine therapy that is associated with poor patient survival. Specifically, in a substantial number of cases, prolonged treatment with endocrine therapy creates the development of resistant tumor cells and, consequently, tumor relapse, which manifests as metastatic disease that is extremely difficult to manage. Recently, deep DNA sequencing has identified somatic mutations at specific sites in the ERα gene (ESR1) in a large subset of patients with breast cancers that have spread. Specifically, Y537S and D538G mutations make ERα resistant to current endocrine therapy and therefore, it is important to develop a novel targeted therapy to address these clinical challenges by inhibiting ERα mutant proteins using next-generation ERα antagonist. Our long-term goal is to develop more effective and safer small molecule drugs that block constitutively active mutant ER for treating endocrine resistant metastatic breast cancer and have the potential to significantly improve current therapeutic targeting strategies. The short-term goal of this R21 application is to identify and develop specific drug-like probes and nominate preclinical candidates to target ER mutant protein by using a DNA-encoded chemical library (DEL) screening platform. The objective of this proposal will be evaluated by addressing the following specific aims: 1. We will perform DNA-encoded chemical libraries screen to identity small-molecule binders to the ligand-binding domain of mutant ERα protein. 2. We will validate and prioritize lead compounds by using biochemical and functional studies. Our central hypothesis is that small molecule antiestrogens with high affinity and specificity for ERα mutants can inhibit ERα mutant function in breast cancer. This research will lay the groundwork for more detailed follow up studies for future applications. After successful execution of this proposed research plan, we expect to have identified lead compounds for mutant ER and that can be used for future pre- clinical and clinical studies.