Identifying primary targets of bumped kinase inhibitor derived compounds to improve utility as therapy for castration resistant prostate cancer

项目总结/摘要 去势抵抗性前列腺癌（CRPC）不可避免地逃避主要治疗， 雄激素受体（AR）依赖。我们正在重新定位碰撞激酶抑制剂（BKI），最初 旨在抑制弓形虫和隐孢子虫。一类BKI衍生化合物 （BKIDC）通过阻断雄激素受体（AR）信号传导，将AR阳性CRPC细胞置于 G1期细胞周期阻滞，阻断其增殖，并抑制糖酵解衍生的ATP产生。而且我们 安全性和药代动力学数据表明，BKIDC是可以合理开发的化合物， 用于治疗CRPC的药物。重要的是，结构-活性关系研究表明，BKIDCs 似乎通过脱靶效应在前列腺癌中表现出它们的抗增殖活性（不一定如 激酶抑制剂），这需要进一步研究其作用机制（MOA）。在本提案中，我们 将确定BKIDC在AR阳性前列腺癌细胞系中作用的主要位点， 假设驱动和无偏见的“组学”方法。我们将进一步验证和表征潜在的 通过药理学和遗传学操作的靶点。通过完成拟议的研究，我们将学习MOA 并准备采取进一步措施将BKIDC带入临床。

Project Summary/Abstract Castration-resistant prostate cancer (CRPC) that inevitably escapes primary therapies most often retains dependency on androgen receptor (AR). We are repositioning bumped kinase inhibitors (BKIs), originally designed to inhibit Toxoplasma gondii and Cryptosporidium parvum. A class of BKI-derived compounds (BKIDCs) target lethal CRPC by blocking androgen receptor (AR) signaling, placing AR positive CRPC cells in G1 cell cycle arrest to block their proliferation, and inhibiting glycolysis-derived ATP production. Moreover, our safety and pharmacokinetics data indicate that BKIDCs are compounds that can be reasonably developed as a drug for the treatment of CRPC. Importantly, structure–activity relationship studies revealed that BKIDCs appear to exhibit their antiproliferative activities in prostate cancer through off-target effects (not necessarily as kinase inhibitors), which warrants further investigation of their mechanism of action (MOA). In this proposal we will determine the primary sites of BKIDCs’ action in AR-positive prostate cancer cell lines through both hypothesis-driven and unbiased “-Omics” approaches. We will further validate and characterize potential targets by pharmacological and genetic manipulation. By completing the proposed studies, we will learn MOA of BKIDCs and be ready to take further steps to bring BKIDCs to clinic.