With more than 450 members, the solute carrier (SLC) group of proteins represents the largest class of transporters encoded in the human genome. Their several-pass transmembrane domain structure and hydrophobicity contribute to the orphan status of many SLCs, devoid of known cargos or chemical inhibitors. We report that SLC proteins belonging to different families and subcellular compartments are amenable to induced degradation by heterobifunctional ligands. Engineering endogenous alleles via the degradation tag (dTAG) technology enabled chemical control of abundance of the transporter protein, SLC38A2. Moreover, we report the design of d9A-2, a chimeric compound engaging several members of the SLC9 family and leading to their degradation. d9A-2 impairs cellular pH homeostasis and promotes cell death in a range of cancer cell lines. These findings open the era of SLC-targeting chimeric degraders and demonstrate potential access of multi-pass transmembrane proteins of different subcellular localizations to the chemically exploitable degradation machinery.

溶质载体 (SLC) 蛋白质组拥有 450 多个成员，代表了人类基因组中编码的最大一类转运蛋白。它们的多次跨膜结构域结构和疏水性导致许多 SLC 处于孤儿状态，缺乏已知的货物或化学抑制剂。我们报告说，属于不同家族和亚细胞区室的 SLC 蛋白易于被异双功能配体诱导降解。通过降解标签 (dTAG) 技术改造内源等位基因，可以对转运蛋白 SLC38A2 的丰度进行化学控制。此外，我们报告了 d9A-2 的设计，这是一种嵌合化合物，与 SLC9 家族的几个成员结合并导致其降解。 d9A-2 会损害细胞 pH 稳态并促进一系列癌细胞系的细胞死亡。这些发现开启了 SLC 靶向嵌合降解剂的时代，并证明了不同亚细胞定位的多次跨膜蛋白有可能进入化学可利用的降解机制。