Small Molecule Inhibitors of Mdm2 E3 Ubiquitin Ligase Activity for Cancer Therapy

描述(由申请人提供)：肿瘤药物发现的靶向蛋白质降解途径最近已被蛋白酶体抑制剂(Bortezomib)在治疗血癌方面的成功所证实。然而，Bortezomib有副作用，癌症患者也可能对该药物产生抗药性。我们已经开发了一种理论基础和独特的策略来确定在蛋白质降解途径中比蛋白酶体更有选择性地发挥作用的新药候选。我们将利用途径上游的一类酶，称为E3泛素连接酶，用于药物抑制--由于每个E3作用于的底物比蛋白酶体少得多，我们预计将开发毒性较低的药物。尽管它们作为药物靶点的潜力很大，但发现E3抑制剂并将其带到临床上仍然是一个尚未满足的挑战。为了实现这些目标，我们设计了一种创新的方法，旨在确定MDM2的抑制剂，MDM2是肿瘤抑制蛋白P53的主要E3连接酶-MDM2的抑制已知会导致细胞中P53蛋白水平的增加，并有望具有药理学意义。然后，我们发现的MDM2抑制剂将接受早期药物开发的概念验证研究。具体地说，在对MDM2抑制剂进行靶向生化筛选之后，表现出理想的药物样特征并比其他E3连接酶具有选择性的最有效的打击将经历最初的药物化学努力。然后，将对表现最好的化合物类似物进行表征，以确定其能否产生预期的生物学和治疗效果。最后，我们将使用生化和结构生物学的方法来研究它们抑制E3的机制，随后将进行第二轮药物化学和验证研究。相关性：MDM2癌蛋白已被广泛验证为肿瘤药物靶点。它在7%的人类癌症中被放大或过度表达，估计仅在美国每年就会影响10万名新患者。然而，目前还没有针对MDM2或其他E3连接酶的药物处于临床试验或市场上。因此，具有抗肿瘤特性的MDM2 E3连接酶活性抑制剂的发现将代表着癌症治疗药物开发的重大创新。

DESCRIPTION (provided by applicant): Targeting protein degradation pathways for Oncology drug discovery has recently been validated by the success of the proteasome inhibitor (bortezomib) in the treatment of blood cancers. However, bortezomib has side effects, and cancer patients can also develop resistance to the drug. We have developed a rationale and unique strategy to identify new drug candidates that act more selectively than the proteasome in protein degradation pathways. We will exploit a class of enzymes upstream in the pathway, known as E3 ubiquitin ligases, for drug inhibition-since each E3 acts on much fewer substrates than the proteasome, we expect less toxic drugs to be developed. Despite their great potential as drug targets, discovering and bringing E3 inhibitors to the clinic have remained unmet challenges. To achieve these goals, we have designed an innovative approach with the aim to identify inhibitors of Mdm2, the main E3 ligase for the tumor suppressor protein p53 --Mdm2 inhibition is known to cause an increase in p53 protein levels in cells and is expected to be pharmacologically relevant. The Mdm2 inhibitors we find will then undergo proof-of-concept studies for early-stage drug development. Specifically, following target-based biochemical screens for Mdm2 inhibitors, the most potent hits that exhibit desirable drug-like features and are selective over other E3 ligases will undergo initial medicinal chemistry efforts. Top-performing compound analogs will then be characterized for the ability to elicit the predicted biological and therapeutic effects. Finally, we will investigate their mechanism of E3 inhibition using biochemical and structural biology approaches, followed by a second round of medicinal chemistry and validation studies. Relevance: The Mdm2 oncoprotein has been widely validated as an oncology drug target. It is amplified or overexpressed in 7% of all human cancers, estimated to impact 100,000 new patients every year in the U.S. alone. However, no drugs targeting Mdm2 or other E3 ligases are currently in clinical trials or in the market. The discovery of inhibitors of Mdm2 E3 ligase activity with anti-tumor properties will thus represent a significant innovation in the development of drugs for the treatment of cancer.