Targeting the MLL complex in Castration Resistant Prostate Cancer

项目摘要 转移性去势抵抗性前列腺癌（CRPC）是一种致死性疾病，估计每年约有30，000例 大多数CRPC是由雄激素受体（AR）信号传导驱动的， 是转移性CRPC的关键治疗靶点。尽管第二代的发展 靶向雄激素受体信号传导的治疗剂，对雄激素消融治疗的抗性（例如， Enzalutamide和阿比特龙）和AR转录活性增加是转移性CRPC的主要驱动因素， 强调了对新疗法的明确需求。最近，我们发现混合系白血病 (MLL)MLL蛋白复合物作为AR的共激活剂起作用，并且MLL复合物与AR的相互作用是 由menin介导，menin是MLL募集到靶基因所需的支架蛋白。组件拆卸 MLL复合物以及抑制menin-MLL与我们开发的小分子的相互作用 消除AR介导的信号传导并抑制AR介导的基因转录。我们还证明 用靶向MLL复合物的小分子抑制剂治疗有效地和选择性地抑制 前列腺癌细胞的增殖，并导致CRPC中体内肿瘤生长的抑制 异种移植模型。根据我们的研究结果，我们假设MLL复合体代表了一种有吸引力的 CRPC中的治疗靶点，并且通过阻断menin-MLL相互作用来抑制该复合物可以 为晚期前列腺癌提供新的治疗策略。本提案的总体目标是 开发非常有效的小分子抑制剂，靶向MLL复合物，在前列腺中具有改善的效力 癌症模型和优化的药物性质，并提供令人信服的科学依据，包括 详细的机制见解，以促进这些化合物作为一种新的潜在治疗方法的发展， 晚期前列腺癌为了实现这一目标，我们提出了三个具体目标：目标1：开发高效的 在前列腺癌中具有显著改善效力的menin-MLL相互作用的小分子抑制剂 模型和最佳的体内特性。在目标2中，我们提出研究药理学的机制， 在目的3中，我们将评估MLL复合物在前列腺癌细胞中的体内功效， menin-MLL抑制剂在小鼠前列腺癌模型中的作用，并研究menin-MLL抑制剂的耐药机制。 在前列腺癌模型中对这些化合物的反应。在成功完成该项目后，我们 期望鉴定有希望的候选化合物，其可以进一步开发用于临床用途以治疗 转移性CRPC。

Project Summary Metastatic castration-resistant prostate cancer (CRPC) is a lethal disease leading to about 30,000 estimated annual deaths in U.S. The majority of CRPCs are driven by androgen receptor (AR) signaling, which represents a key therapeutic target in metastatic CRPC. Despite development of second generation therapeutics targeting the androgen receptor signaling, the resistance to androgen ablation therapies (e.g. enzalutamide and abiraterone) and increased AR transcriptional activity are major drivers of metastatic CRPC, emphasizing a clear need for novel therapies. Recently, we discovered that the Mixed Lineage Leukemia (MLL) protein complex functions as a co-activator of AR and that the interaction of MLL complex with AR is mediated by menin, a scaffold protein required for MLL recruitment to target genes. Knockdown of components of the MLL complex as well as inhibition of the menin-MLL interaction with small molecules we developed abrogates the AR-mediated signaling and inhibits the AR-mediated gene transcription. We also demonstrated that treatment with a small molecule inhibitor targeting the MLL complex effectively and selectively inhibits proliferation of the prostate cancer cells and leads to a suppression of the in vivo tumor growth in the CRPC xenograft models. Based on our findings, we hypothesize that the MLL complex represents an attractive therapeutic target in CRPC and that inhibition of this complex by blocking the menin-MLL interaction may provide a novel therapeutic strategy for advanced prostate cancer. The overall goal of this proposal is to develop very potent small molecule inhibitors targeting the MLL complex with improved potency in prostate cancer models and optimized drug-like properties and to provide a compelling scientific rationale, including detailed mechanistic insight, to facilitate advancing of these compounds as a novel potential treatment for advanced prostate cancer. To achieve this goal, we propose three specific aims: Aim 1: Develop highly potent small molecule inhibitors of the menin-MLL interaction with significantly improved potency in prostate cancer models and optimal in vivo properties. In Aim 2, we propose to study the mechanism of pharmacologic inhibition of the MLL complex in prostate cancer cells, while in Aim 3 we will assess the in vivo efficacy of the menin-MLL inhibitors in mice models of prostate cancer and investigate the mechanism of resistance of response to these compounds in prostate cancer models. Upon successful completion of this project we expect to identify promising candidate compound(s) that could be further developed for clinical use to treat metastatic CRPC.