Targeting PTEN Null Tumors via Inhibition of the p110beta Isoform of PI3 Kinase

描述（由申请人提供）：IA类磷脂酰肌醇3激酶（PI3K）信号轴可能是人类癌症中最常激活的途径。响应受体酪氨酸激酶（rtk）的激活，g蛋白偶联受体（gpcr）或Ras， IA类pi3k，由三种催化亚型组成，称为p110？, p110 ?和p110吗?，激活产生主要的细胞内脂质信号，磷脂酰肌醇3,4,5-三磷酸（PIP3），这是多种细胞过程所必需的。肿瘤抑制因子PTEN是一种脂质磷酸酶，可使PIP3去磷酸化，从而拮抗PI3K的作用并调节PI3K通路的活性。肿瘤中的通路激活通常是通过激活p110？或通过PTEN肿瘤抑制因子的缺失。重要的是，PI3K酶非常适合药理干预，使其成为癌症治疗的有吸引力的靶点。事实上，各大制药公司的许多PI3K抑制剂已经进入了癌症治疗的临床试验，但这些抑制剂大多针对所有p110亚型，这可能会导致PI3K在正常生理中的重要作用引起的副作用。虽然同种异构体特异性抑制剂正在进一步开发，但大多数抑制剂针对p110？（针对实体瘤）还是p110？(血液恶性肿瘤)。我们认为，制药公司未能开发出p110？特殊技能抑制剂。我们和其他人最近已经证明，由PTEN缺失驱动的肿瘤特别依赖于p110？不是p110 ?。这个项目的总体目标是生成p110？特异性抑制剂作为新的靶向治疗多种PTEN突变的癌症。为此，我们组建了一个科学家团队，为实现这一目标而优化。我们团队用于评估PI3K信号的独特试剂，加上我们在蛋白质化学，x射线晶体学，药物化学和动物模型方面的专业知识，使我们能够有效地开发p110？抑制剂在未来两年的临床试验期间。我们的具体目标是建立基于细胞的系统和遗传模型，以确定p110？在不同组织类型中PTEN驱动的肿瘤发生和p110？-特异性抑制剂，以纯化大量活性p110？用于酶分析和结晶学，并开展化学活动，设计和评估p110？利用细胞和动物模型以及p110?复合物的结构信息对这些支架进行抑制和优化还有一种抑制剂。

DESCRIPTION (provided by applicant): The class IA phosphatidylinositol 3 kinase (PI3K) signaling axis is perhaps the most frequently activated pathway in human cancer. In response to the activation of receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs) or Ras, class IA PI3Ks, consisting of three catalytic isoforms termed p110?, p110? and p110?, are activated to generate the primary intracellular lipid signal, phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is essential for multiple cellular processes. The tumor suppressor PTEN, a lipid phosphatase, dephosphorylates PIP3, thereby antagonizing the actions of PI3K and regulating the PI3K pathway activity. Pathway activation in tumors is most commonly achieved through activating mutations in p110? isoform or via loss of the PTEN tumor suppressor. Importantly, PI3K enzymes are highly suited for pharmacological intervention, making them attractive targets for cancer therapy. In fact, there are a number of PI3K inhibitors from major pharmaceutical companies that have entered clinical trials for cancer treatment, but most of these inhibitors target all p110 isoforms, which may cause side effects arising from the essential roles of PI3K in normal physiology. While isoform specific inhibitors are being further developed, most of which are directed toward p110? (for solid tumors) or p110? (Hematological malignancies). We believe that the drug companies have blundered by failing to develop p110?-specific inhibitors. We and others have recently demonstrated that tumors driven by PTEN loss are specifically dependent of p110? not p110?. The broad goal of this project is to generate p110? -specific inhibitors for use as new, targeted therapeutics in diverse cancers featuring PTEN mutations. To this end we have assembled a team of scientists optimized to achieve this goal. Our team's unique reagents for assessing PI3K signaling, coupled with and our expertise in protein chemistry, X-ray crystallography, medicinal chemistry and animal models, position us to effectively develop p110? inhibitors over a two-year time period for future clinical trials. Our specific goals are to generate cell-based systems and genetic models to determine the role of p110? in tumorigenesis driven by PTEN in different tissue types and to test p110? -specific inhibitors, to purify large amounts of active p110? for enzyme assays and crystallography and to pursue a chemistry campaign to design and evaluate new scaffolds for p110? inhibition and optimize 2 of these scaffolds using both cell and animal models and structural information from a complex of p110? and an inhibitor. PUBLIC HEALTH RELEVANCE: Statement of the relevance of the project to public health: The PTEN tumor suppressor is genetically or epigenetically silenced at high frequency in may types of human cancer. Recent data suggests that tumors driven by PTEN loss are dependent on the activity of a particular isoform of PI3K termed p110?. This project is designed to speed development of p110? inhibitors and hence could have a positive impact on many cancer patients.