*Article* **Modulation of the Endomembrane System by the Anticancer Natural Product Superstolide/ZJ-101**

**Phillip R. Sanchez 1,2, Sarah A. Head 2, Shan Qian 3, Haibo Qiu 3, Avishek Roy 3, Zhendong Jin 3, Wei Zheng 1,\* and Jun O. Liu 2,\***


**Abstract:** Marine natural products represent a unique source for clinically relevant drugs due to their vast molecular and mechanistic diversity. ZJ-101 is a structurally simplified analog of the marine natural product superstolide A, isolated from the New Caledonian sea sponge *Neosiphonia Superstes*. The mechanistic activity of the superstolides has until recently remained a mystery. Here, we have identified potent antiproliferative and antiadhesive effects of ZJ-101 on cancer cell lines. Furthermore, through dose–response transcriptomics, we found unique dysregulation of the endomembrane system by ZJ-101 including a selective inhibition of O-glycosylation via lectin and glycomics analysis. We applied this mechanism to a triple-negative breast cancer spheroid model and identified a potential for the reversal of 3D-induced chemoresistance, suggesting a potential for ZJ-101 as a synergistic therapeutic agent.

**Keywords:** natural product; superstolide; glycomics; transcriptomics; phenotypic analysis; 3D spheroid
