Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e., autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic cancer, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer.

Significance: This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy. Cancer Discov; 7(11); 1266–83. ©2017 AACR.

See related commentary by Towers and Thorburn, p. 1218.

This article is highlighted in the In This Issue feature, p. 1201

溶酶体在癌症代谢中起双重作用，执行分解代谢程序（即自噬和巨噬细胞增多），同时促进mTORC1依赖性合成代谢。抗疟疾化合物（例如氯喹或奎纳克林）已被用作溶酶体抑制剂，但不能抑制mTOR信号传导。此外，尚未确定这些试剂的分子靶标。我们报告了一种新型的二聚体抗疟疾药物的屏幕，该屏幕将二聚体喹那林（DQ）识别为有效的抗癌化合物，同时抑制了mTOR和自噬。DQ接头的中央氮甲基化可增强溶酶体的定位和效力。一种原位光亲和力下拉确定为DQ661的分子目标棕榈酰蛋白硫酯酶1（PPT1）。PPT1抑制通过棕榈酰化蛋白的快速积累同时损害mTOR和溶酶体分解代谢。DQ661抑制体内黑色素瘤，胰腺癌和结肠直肠癌小鼠模型的肿瘤生长，可以安全地与化学疗法联合使用。因此，溶酶体导向的PPT1抑制剂代表了一种同时靶向mTORC1和溶酶体分解代谢的新方法。

意义：这项研究确定了增加其溶酶体特异性的二聚体化合物的化学特征，以及这些化合物的新分子靶标，将这些化合物重新归类为靶向疗法。靶向PPT1以不同于催化抑制剂的方式阻断mTOR信号传导，同时抑制自噬，从而为癌症治疗提供了新的策略。巨蟹座Discov; 7（11）；1266–83。©2017 AACR。

参见Towers和Thorburn的相关评论，第1页。1218。

本文在本期功能中突出显示。1201