Small-Molecule Endoplasmic Reticulum Stress Inducer Triggers Apoptosis in Cancer Cells

Endoplasmic reticulum (ER) is highly critical for the sub-cellular protein synthesis, post-translational modifications and myriads of signalling pathways to maintain cellular homeostasis. Consequently, dysregulation in the ER functions leads to the ER stress in different pathological situations including cancer. Hence, exploring small molecules to induce ER stress emerged as one of the unorthodox strategies for future cancer therapeutics. However, development of ER targeted novel small molecules remains elusive due to the dearth of ER targeting moieties. Herein we have synthesized a small library of 3-methoxy-pyrrole-enamine through a concise strategy. Screening of this library in cervical (HeLa), colon (HCT-116), breast (MCF7) and lung cancer (A549) cells identified a novel small molecule which localized into the ER of the HeLa cervical cancer cells within 3 h, induced ER stress through the increased expression of ER stress markers (CHOP, IRE1α, PERK, BiP and Cas-12) and triggered the programmed cell death (apoptosis) leading to remarkable HeLa cell killing. This novel small molecule can be explored further as a tool to understand the chemical biology of ER towards the development of ER targeted cancer therapeutics.