Substrate Specificity Determinants in Cancer-related Solute Carrier Transporters

描述（由申请人提供）：细胞代谢的改变支持细胞的快速生长和增殖-癌症的关键标志。溶质载体（SLC）转运蛋白是介导溶质（如代谢物和药物）跨膜运动的膜蛋白，也可以在癌症代谢途径中协同发挥作用。例如，氨基酸转运蛋白LAT-1和ASCT 2在神经胶质瘤中高度上调，其中它们在向生长的肿瘤细胞供应必需氨基酸中起关键作用，所述必需氨基酸用作构建生物质的营养物和增强增殖的信号传导分子。我们的广泛目标是通过综合实验和计算方法，描述选定的癌症相关转运蛋白家族中的底物特异性决定簇，从而了解癌症机制。首先，我们将鉴定新的配体，包括三种癌症相关SLC转运蛋白（即，GLUT 1，ASCT 2和LAT-1），使用比较建模，虚拟筛选和化学信息学方法，然后进行实验验证（由合作者进行）。本研究的结果将揭示转运蛋白的未知功能，并为进一步研究其功能提供新的化学工具。其次，我们将使用结构比较方法和预测的转运蛋白-配体复合物的分析来定义结构相关转运蛋白的底物特异性规则。特异性决定因素将用于合理化和预测遗传变异对转运蛋白功能的影响。第三，我们将制定合理设计 本发明涉及癌症代谢途径中转运蛋白的多药理学配体，并检查所发现的配体对多形性胶质母细胞瘤（GBM）细胞系的抗增殖作用。我们将通过化学相似性方法预测以前未知的蛋白质-小分子相互作用，进一步确定转运蛋白及其配体在癌症中的作用。最后，根据我们的研究结果，我们将合理化正常和转化细胞的代谢途径之间的差异和共性。表征关键膜转运蛋白及其小分子配体之间的相互作用将有助于我们理解溶质如何穿过细胞和细胞器的膜进行转运，这对于许多生命过程至关重要。此外，描述对癌症代谢重要的蛋白质中的底物特异性将提供化学工具，使我们能够了解受干扰的代谢网络如何与癌症相关，并发现新的线索，用于设计对新型癌症药物靶点具有优化亲和力的小分子。最终，我们的研究结果可能是设计癌症药物的重要一步。

DESCRIPTION (provided by applicant): Alterations in cell metabolism support rapid growth and proliferation of cells - key hallmarks of cancer. Solute Carrier (SLC) transporters are membrane proteins that mediate the movement of solutes such as metabolites and drugs across membranes, and can also function cooperatively in cancer metabolism pathways. For exam- ple, the amino acid transporters LAT-1 and ASCT2 are highly upregulated in glioma, where they play a key role in supplying growing tumor cells with essential amino acids that are used as nutrients to build biomass and signaling molecules to enhance proliferation. Our broad goal is to understand cancer mechanisms, by de- scribing the substrate specificity determinants in selected cancer-related transporter families via an integrated experimental and computational approach. First, we will identify novel ligands including endogenous metabolites and prescription drugs for three cancer- related SLC transporters (i.e., GLUT1, ASCT2, and LAT-1), using comparative modeling, virtual screening, and chemoinformatics methods, followed by experimental validation (performed by collaborators). The results obtained in this Aim will reveal unknown functions of the transporters and provide novel chemical tools to further characterize their functions. Second, we will define rules for substrate specificity of structurally related transporters, using structural comparison methods and analysis of the predicted transporter-ligand complexes. The specificity determinants will be used to rationalize and predict the impact of genetic variation on trans- porter function. Third, we will develop methods to rationally design polypharmacological ligands for transporters in cancer-metabolism pathways and examine the anti-proliferative effect of the discovered ligands on glioblastoma multiforme (GBM) cell lines. We will further establish the role of the transporters and their ligands in cancer, by predicting previously unknown protein-small molecule interactions via chemical similarity methods. Finally, based on our results, we will rationalize differences and commonalities between metabolic pathways of normal and transformed cells. Characterizing the interactions between key membrane transporters and their small molecule ligands will con- tribute to our understanding of how solutes get transported across the membranes of cells and organelles, which is essential for many of life's processes. Furthermore, describing substrate specificity in proteins important for cancer metabolism will provide chemical tools that would allow us to understand how perturbed metabolic networks are related to cancer and to discover novel leads for designing small molecules with optimized affinities against novel cancer drug targets. Ultimately, the results obtained in our studies can be a significant step toward designing cancer drugs.