State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China.
J Med Chem. 2021 Jan 14;64(1):629-643. doi: 10.1021/acs.jmedchem.0c01197. Epub 2020 Dec 31.
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 , , and 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 . , compound 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.
在胰腺肿瘤微环境中，激活的胰腺星状细胞（PSCs）会产生细胞外基质（ECM），形成药物渗透的屏障。此外，癌细胞与激活的 PSCs 之间的相互作用促进了肿瘤的生长。维生素 D 受体（VDR）作为促进 PSCs 恢复静息状态的关键调节剂，是治疗胰腺癌的一个有吸引力的治疗靶点。在此，我们报道了基于苯并吡咯戊烷骨架设计和合成的 57 种非甾体 VDR 调节剂。其中，化合物 、 和 表现出优异的 VDR 亲和力和对 PSCs 激活的有效抑制作用，以及对癌细胞与 PSCs 相互作用的有效抑制作用。 ，化合物 与吉西他滨联合使用可有效抑制肿瘤生长，而不会导致高钙血症。总之，我们研究设计的化合物可以重塑肿瘤微环境，有望成为治疗胰腺癌的候选药物。
