Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California.
Cancer Res. 2021 Apr 1;81(7):1883-1895. doi: 10.1158/0008-5472.CAN-20-1540. Epub 2021 Feb 2.
GRP78 (glucose-regulated protein, 78 kDa) is a key regulator of endoplasmic reticulum (ER) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis and folding, which results in significant stress on the ER. To respond to ER stress and maintain cellular homeostasis, cells activate the unfolded protein response (UPR) that promotes either survival or apoptotic death. Cancer cells utilize the UPR to promote survival and growth. In this study, we describe the discovery of a series of novel hydroxyquinoline GRP78 inhibitors. A representative analogue, YUM70, inhibited pancreatic cancer cell growth and showed efficacy in a pancreatic cancer xenograft model with no toxicity to normal tissues. YUM70 directly bound GRP78 and inactivated its function, resulting in ER stress-mediated apoptosis. A YUM70 analogue conjugated with BODIPY showed colocalization of the compound with GRP78 in the ER. Moreover, a YUM70-PROTAC (proteolysis targeting chimera) was synthesized to force degradation of GRP78 in pancreatic cancer cells. YUM70 showed a strong synergistic cytotoxicity with topotecan and vorinostat. Together, our study demonstrates that YUM70 is a novel inducer of ER stress, with preclinical efficacy as a monotherapy or in combination with topoisomerase and HDAC inhibitors in pancreatic cancer. SIGNIFICANCE: This study identifies a novel ER stress inducer that binds GRP78 and inhibits pancreatic cancer cell growth and , demonstrating its potential as a therapeutic agent for pancreatic cancer.
GRP78（葡萄糖调节蛋白，78kDa）是内质网（ER）应激信号的关键调节剂。癌细胞增殖能力强，对蛋白质合成和折叠的需求高，这导致 ER 承受巨大压力。为了应对 ER 应激并维持细胞内稳态，细胞激活未折叠蛋白反应（UPR），促进细胞存活或凋亡。癌细胞利用 UPR 促进存活和生长。在这项研究中，我们描述了一系列新型羟基喹啉 GRP78 抑制剂的发现。代表性类似物 YUM70 抑制胰腺癌细胞生长，并在胰腺癌异种移植模型中显示出疗效，对正常组织无毒性。YUM70 直接与 GRP78 结合并使其失活，导致 ER 应激介导的细胞凋亡。与 BODIPY 缀合的 YUM70 类似物显示该化合物与 GRP78 在 ER 中的共定位。此外，合成了一种 YUM70-PROTAC（蛋白水解靶向嵌合体），以迫使胰腺癌细胞中 GRP78 的降解。YUM70 与拓扑替康和伏立诺他显示出强烈的协同细胞毒性。总之，我们的研究表明，YUM70 是一种新型的 ER 应激诱导剂，具有作为单一疗法或与拓扑异构酶和组蛋白去乙酰化酶抑制剂联合治疗胰腺癌的临床前疗效。意义：本研究鉴定了一种新型的内质网应激诱导剂，它与 GRP78 结合并抑制胰腺癌细胞生长，表明其作为治疗胰腺癌的潜在药物的潜力。
