Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

作者：Zisheng Kang, Cong Wang, Tong Yu, Yanyi Li, Yi Gao, Siyuan Hou, Meixi Hao, Xiaolin Han, Bin Wang, Qianqian Wang, Can Zhang · 发表于：Journal of Medicinal Chemistry · 年份：2020 · DOI：10.1021/acs.jmedchem.0c01197 · 被引用次数：34 · 研究领域：Pancreatic and Hepatic Oncology Research、Neuroendocrine Tumor Research Advances、Vitamin D Research Studies

In a pancreatic tumor microenvironment, activated pancreatic stellate cells (PSCs) produce extracellular matrix (ECM) to form a barrier to drug penetration. Moreover, the interaction between cancer cells and activated PSCs promotes the tumor growth. Vitamin D receptor (VDR), as a key regulator to promote the recovery of PSCs to the resting state, is an attractive therapeutic target for pancreatic cancer. Herein, we reported the design and synthesis of 57 nonsecosteroidal VDR modulators based on the skeleton of phenyl-pyrrolyl pentane. Among them, compounds C4, I5, and I8 exhibited excellent VDR affinity and effective inhibition of the activation of PSCs, as well as potent suppression of the interaction between cancer cells and PSCs in vitro . In vivo, compound I5 combined with gemcitabine achieved efficacious antitumor activity without causing hypercalcemia. In conclusion, the compounds designed in our study can remodel the tumor microenvironment and are expected to be candidates for the treatment of pancreatic cancer.