Solute carrier proteins (SLCs) are a superfamily of transmembrane transporters that control essential physiological functions such as nutrient uptake, ion transport, and cellular waste elimination. Although many SLCs are associated with various disease states and are considered "druggable," they remain underexplored as a drug target class. One subfamily of SLCs that has gained attention for its therapeutic potential is the monocarboxylate solute transporter family. The monocarboxylate transporter protein 1 (MCT1) is a passive transporter of lactate and has gained significant attention for its role(s) in cancer progression; moreover, upregulation of MCT1 connotes poor patient outcome and survival. Consequently, small molecule inhibitors of MCT1 activity are being pursued as anticancer therapies. However, typical for members of this SLC subfamily, there is a paucity of potent and selective modulators of MCT1. This is in part due to methods used for their identification, typically relying on the use of radiolabeled substrate tracing. In addition to the safety concerns associated with radioactivity, this methodology is also expensive and time consuming. In this study, we describe the use of an MCT1 cytotoxic substrate as a tool to enable the development of a nonradioactive cell-based homogeneous assay that facilitates industry-scale high-throughput screening (HTS) of large compound libraries to identify novel MCT1 inhibitors to interrogate the therapeutic potential of MCT1. Our assay is robust, reproducible, HTS amenable, and establishes a conceptually novel way to identify chemical probes to investigate the therapeutic potential of SLC proteins.

中文翻译：

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一种非放射性高通量筛选兼容的基于细胞的测定法，用于鉴定单羧酸盐转运蛋白1的抑制剂。

溶质载体蛋白（SLC）是跨膜转运蛋白的超家族，其控制基本的生理功能，例如营养吸收，离子转运和消除细胞废物。尽管许多SLC与各种疾病状态相关联并且被认为是“可服用的”，但它们仍未充分开发为药物靶标类别。SLC的一个亚家族因其治疗潜力而受到关注，是单羧酸盐溶质转运蛋白家族。单羧酸转运蛋白1（MCT1）是乳酸的被动转运蛋白，因其在癌症进展中的作用而受到广泛关注。此外，MCT1的上调表示患者预后和生存率较差。因此，正在寻求MCT1活性的小分子抑制剂作为抗癌疗法。然而，对于该SLC亚家族的成员而言，典型的是，MCT1的有效和选择性调节剂很少。这部分是由于用于其识别的方法，通常依赖于使用放射性标记的底物示踪剂。除了与放射性有关的安全问题外，该方法还昂贵且费时。在这项研究中，我们描述了使用MCT1细胞毒性底物作为一种工具来开发基于非放射性细胞的均相测定方法，该方法有助于对大型化合物库进行工业规模的高通量筛选（HTS），以鉴定新型的MCT1抑制剂。询问MCT1的治疗潜力。我们的分析功能强大，可重现，适合HTS，并建立了一种概念上新颖的方法来鉴定化学探针以研究SLC蛋白的治疗潜力。