Targeting the MLL complex in Castration Resistant Prostate Cancer

项目摘要 转移性去势抵抗前列腺癌(CRPC)是一种致命的疾病，估计导致约30,000人死亡 美国的年死亡率大多数CRPC是由雄激素受体(AR)信号驱动的，它 代表了转移性CRPC的关键治疗靶点。尽管有第二代的发展 针对雄激素受体信号转导的治疗，对雄激素消融治疗的抵抗(例如 苯扎鲁胺和阿比特龙)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，我们发现混合血统白血病 (MLL)蛋白复合体是AR的共同激活剂，MLL复合体与AR的相互作用 在脑膜素的介导下，MLL招募到靶基因所需的支架蛋白。零部件的拆卸 以及抑制我们开发的小分子与MLL的相互作用 取消AR介导的信号转导，抑制AR介导的基因转录。我们还演示了 以MLL复合体为靶点的小分子抑制剂治疗有效和选择性地抑制 前列腺癌细胞的增殖和体内肿瘤生长的抑制 异种移植模型。根据我们的发现，我们假设MLL复合体代表着一种有吸引力的 CRPC治疗靶点以及通过阻断脑膜素-MLL相互作用来抑制该复合体可能 为晚期前列腺癌提供一种新的治疗策略。这项提案的总体目标是 开发针对MLL复合体的非常有效的小分子抑制剂，提高其在前列腺中的效力 癌症模型和优化的类药物特性，并提供令人信服的科学理由，包括 详细的机理洞察，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 显著提高前列腺癌治疗效果的脑膜素-MLL相互作用的小分子抑制剂 模型和最佳体内特性。在目标2中，我们建议研究其药理作用机制。 抑制前列腺癌细胞中的MLL复合体，而在目标3中，我们将评估 MENIN-MLL抑制剂在小鼠前列腺癌模型中的作用及其耐药机制的研究 前列腺癌模型中对这些化合物的反应。在这个项目成功完成后，我们 希望找到有希望的候选化合物(S)，可以进一步开发用于临床治疗 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.