Development of Novel BET Bromodomain Inhibitors for the Treatment of Advanced

目前，转移性去势抵抗前列腺癌(Crpc)总是致命的。 疾病。绝大多数CRPC依赖于雄激素受体(AR)信号并受其驱动。而当 最近的进展导致了针对雄激素的第二代治疗药物的开发 对于信号轴(如苯扎鲁胺和阿比特龙)，对这些新药物的反应往往不持久。 因此，有一种明确而紧迫的需要，需要开发针对这种疾病的全新治疗方法。 AR轴。最近，我们的团队发现了一种新的策略，通过抑制AR信号轴 含有4(BRD4)的溴结构域，是BET家族的保守成员 转录共激活子(在《自然》杂志上修订)。我们发现AR与BRD4在物理上相互作用，并且 用BET-溴域抑制剂JQ1处理会破坏AR-BRD4相互作用和AR 招募到靶向基因座。与AR直接拮抗剂苯扎鲁胺相比，BET溴域 抑制剂在抑制AR介导的基因转录方面要有效得多，包括AR的诱导 TMPRSS2等目标：ERG和PSA。值得注意的是，JQ1也比苯扎鲁胺更有效 抑制CRPC异种移植瘤生长。根据我们的发现，我们假设BET溴域 抑制是靶向AR轴和治疗晚期前列腺癌的一种很有前途的方法。我们的目标 在这个孢子项目中是开发一种有效的BET-溴域小分子抑制剂(BET抑制剂) 通过以下特定目标优化用于治疗晚期前列腺癌的体内特性： 目的1：开发一种体内性质优化的高效、选择性BET抑制剂 目的2：用新型BET抑制剂询问AR-BRD4信号轴。 目的3：在体内和体外肿瘤模型中建立BET溴域抑制剂的有效性，以及 开发反应的生物标记物。 在成功完成目标后，我们预计将提名有希望的候选人(S)，这可能是 进一步开发用于临床治疗转移性CRPG。这个项目的最终目标是引入BET 基于对其作用机制的独特理解，溴域抑制剂可作为CRPC的一种新疗法 行动。

Currently, metastatic castration-resistant prostate cancer (CRPC) is invariably and unfortunately a lethal disease. The vast majority of CRPC is dependent upon and driven by androgen receptor (AR) signaling. While recent advances have resulted in the development of second generation therapeutics targeting the androgen signaling axis (e.g. enzalutamide and abiraterone), the responses to these new agents are often not durable. Thus, there is a clear and urgent need to develop completely new therapeutic approaches directed against the AR axis. Recently, our team identified a novel strategy for targeting the AR signaling axis via inhibition of bromodomain containing 4 (BRD4), a conserved member of the bromodomain and extraterminal (BET) family of transcriptional co-activators (In Revision at Nature). We discovered that AR physically interacts with BRD4, and that treatment with the BET-bromodomain inhibitor JQl disrupts the AR-BRD4 interaction as well as AR recruitment to target gene loci. Compared to the direct AR antagonist enzalutamide, BET bromodomain inhibitors are much more effective in inhibition of AR-mediated gene transcription, including induction of AR targets such as TMPRSS2:ERG and PSA. Significantly, JQ1 was also more effective than enzalutamide in inhibiting the growth of CRPC xenografts. Based upon our findings, we hypothesize that BET bromodomain inhibition is a promising approach for targeting the AR axis and for treating advanced prostate cancer. Our goal in this SPORE project is to develop a potent BET-bromodomain small-molecule inhibitor (BET inhibitor) with optimized in vivo properties for the treatment of advanced prostate cancer through the following specific aims: Aim 1: Develop a highly potent and selective BET inhibitor with optimized in vivo properties Aim 2: Interrogate the AR-BRD4 signaling axis with novel BET inhibitors. Aim 3: Establish the efficacy of BET bromodomain inhibitors using in vivo and ex vivo tumor models, and develop biomarkers of response. Upon successful completion of the Aims, we expect to nominate promising candidate(s) that could be developed further for clinical use to treat metastatic CRPG. The ultimate goal of this project is introduce BET bromodomain inhibitors as a novel therapy for CRPC based on a unique understanding of its mechanism of action.