Anticancer peptide therapeutics

尽管几十年来制药公司的研究和开发（R&D）支出呈指数级增长， 在制药行业，FDA每年批准的新药平均数量为25种左右，一直停滞不前。的 研发支出失控的不可持续趋势直接导致了全球医疗保健成本的飙升， 国家，强调迫切需要新的药物目标和类别。蛋白质相互作用（PPI）控制所有 细胞过程的各个方面，被认为是药物发现和最终药物靶点的“圣杯”， 疾病干预。不幸的是，现有的两大类药物--低分子量化合物 并且抗体可有效干扰细胞内PPI。另一方面，虽然小肽能够 由于它们对蛋白水解的敏感性， 体内降解。对于这个药物发现中的长期谜团，一个明智的解决方案是侧链装订的L-肽 和抗蛋白水解的D-肽。拮抗MDM 2/MDMX以激活p53是最有前途的方法之一。 抗癌治疗的治疗范例。我们最近开发了一系列高亲和力的L-和D-肽 在体外和体内以p53-和MDM 2-依赖的方式有效抑制肿瘤生长的MDM 2拮抗剂， 方式然而，为了实现持续和稳健的p53活化和最佳治疗功效，双重特异性 需要MDM 2和MDMX两者的拮抗剂。这项研究的总体目标是开发一种新的... MDM 2和MDMX的亲和性、双特异性和蛋白水解抗性肽拮抗剂作为一种强大的p53- 治疗急性髓性白血病的激活方式-其中TP 53基因突变罕见，MDM 2 和MDMX经常被放大或过度表达。这一项目可能导致在现有的基础上增加新武器 抗癌武器库和广泛影响肽治疗的发展，为靶向分子治疗的许多 其他疾病也是如此。

Despite an exponential increase over decades in research and development (R&D) expenditures by the pharmaceutical industry, the average number of new drugs approved annually by the FDA, 25 or so, has remained stagnant. The unsustainable trend of runaway spending in R&D directly contributes to skyrocketing health care costs across the country, underscoring an urgent need for new drug targets and classes. Protein-protein interactions (PPIs) control all aspects of cellular processes and are considered to be the “Holy Grail” in drug discovery and ultimate drug targets for disease intervention. Unfortunately, neither of the two major classes of existing drugs – low molecular weight compounds and antibodies are effective in interfering with intracellular PPIs. On the other hand, although small peptides are capable of effectively disrupting PPIs, they generally lack drug-like properties due primarily to their susceptibility to proteolytic degradation in vivo. A sensible solution to this long-running enigma in drug discovery is side chain-stapled L-peptides and proteolysis-resistant D-peptides. Antagonizing MDM2/MDMX to activate p53 is one of the most promising therapeutic paradigms for anticancer therapy. We have recently developed a series of high-affinity L- and D-peptide antagonists of MDM2 that effectively suppress tumor growth in vitro and in vivo in a p53- and MDM2-dependent manner. To achieve sustained and robust p53 activation and optimal therapeutic efficacy, however, dual-specificity antagonists of both MDM2 and MDMX are needed. The overall goal of this proposed research is to develop ultrahigh- affinity, dual-specificity, and proteolysis-resistant peptide antagonists of MDM2 and MDMX as a powerful p53- activating modality for the treatment of acute myeloid leukemia – where mutations of the TP53 gene are rare and MDM2 and MDMX are often amplified or over-expressed. This project may lead to the addition of new weapons to the existing anticancer arsenal and broadly impact the development of peptide therapeutics for targeted molecular therapy of many other diseases as well.