Targeting Akt with substrate mimetic antagonists

描述（由申请人提供）：各种癌症的增殖速率和进展增加可与凋亡信号级联中的缺陷直接相关。Akt是一个中央 PI 3 K途径中的蛋白质，通过细胞内底物的失活赋予对凋亡的抗性。Akt的过度活化在超过50%的人类肿瘤的发生和维持中是必不可少的。最常见的包括乳腺癌、卵巢癌、胰腺癌和胃癌，以及特别具有侵袭性的难治性前列腺癌。抑制Akt的激酶活性是治疗这些恶性肿瘤的临床验证策略。然而，大多数针对这一目标的努力集中在从Akt结合口袋中取代内源性ATP的药物上，这种策略通常产生抑制其他同源激酶的混杂的先导化合物。相比之下，我们的实验室致力于开发Akt抑制剂，其特异性靶向蛋白质底物结合裂缝附近。 到ATP站点。这种方法背后的基本原理是Akt的蛋白质-蛋白质相互作用（PPI）区域相对于其他结合位点具有更有辨别力的拓扑结构。Akt与其内源性底物GSK 3b的截短部分结合的最新X射线共晶体结构已经为各种肽前导结构的设计提供了信息。尽管由于广泛的相互作用区域，靶向Akt的PPI结构域可能更困难，但许多令人信服的因素促使我们追求PPI靶向策略，包括（1）在我们的实验室中发现了具有还原肽特征的有效底物模拟先导抑制剂，（2）基于X射线晶体学的结构原理，（3）靶向Akt的广泛临床验证，和（4）缺乏FDA批准的用于治疗癌症的Akt抑制剂。在这里，我们提出了基于结构的设计和合成的一个集中的类似物库的基础上，我们的铅抑制剂，并在体外的全细胞测定的生物学评价。本项目的目的是提供第一个能够选择性靶向Akt依赖性肿瘤细胞的非肽底物模拟抑制剂。我们的长期目标是使用PPI方法开发具有更有利治疗特征的临床候选药物，并将此策略应用于抑制其他致癌激酶。 公共卫生相关性：Akt是一种参与驱动各种癌症发病的信号蛋白。超过50%的人类肿瘤具有某种形式的Akt过度激活。该研究项目的重点是开发一类新的抑制Akt的分子。这项研究的结果可能对依赖于这种和其他激酶信号通路的恶性肿瘤的治疗具有重要意义。

DESCRIPTION (provided by applicant): The increased proliferation rate and progression of various cancers can be directly linked to defects in apoptotic signaling cascades. Akt is a central protein in the PI3K pathway that confers resistance to apoptosis through inactivation of intracellular substrates. Hyperactivation of Akt is essential in the initiation and maintenance of over 50% of all human tumors. The most common include breast, ovarian, pancreatic, and gastric cancers, as well as the particularly aggressive hormone-refractory prostate cancers. Inhibition of the kinase activity of Akt is a clinically validated strategy for the treatment of thse malignancies. However, most efforts directed toward this end focus on agents that displace endogenous ATP from the Akt binding pocket-a strategy that often yields promiscuous lead compounds that inhibit other homologous kinases. In contrast, our laboratory is engaged in the development of Akt inhibitors that specifically target the protein substrate-binding cleft adjacent to the ATP site. The rationale behind this approach is the notion that the protein-protein interaction (PPI) region of Akt harbors a far more discerning topology relative to other binding sites. Recent X- ray co-crystal structures of Akt bound to truncated sections of its endogenous substrate GSK3b have informed the design of various peptide lead structures. Although targeting the PPI domain of Akt is presumably more difficult due to the extensive interaction region, a number of compelling factors have prompted us to pursue a PPI-targeting strategy, including (1) the discovery, in our lab, of a potent substrate mimetic lead inhibitor with reduced peptide character, (2) a structural rationale for refinements based on X-ray crystallography, (3) extensive clinical validation for targeting Akt, and (4) the lack of an FDA-approved Akt inhibitor for the treatment of cancer. Here, we propose the structure-based design and synthesis of a focused library of analogs based on our lead inhibitor, and their biological evaluation in vitro an in whole cell assays. The objective of this project is to provide the first non-peptide substrate mimetic inhibitors capable of selectively targeting Akt-dependant tumor cells. Our longer-term goals are to use a PPI approach to develop clinical candidates with more favorable therapeutic profiles and to apply this strategy to the inhibition of other oncogenic kinases. PUBLIC HEALTH RELEVANCE: Akt is a signaling protein involved in driving the onset of various cancers. Greater than 50% of all human tumors feature some form of Akt hyperactivation. This research project is focused on the development a new class of molecules to inhibit Akt. Results from this study will potentially have important implications for the treatment of malignancies dependant on this and other kinase signaling pathways.