Small Molecular Inhibitors Reverse Cancer Metastasis by Blockading Oncogenic PITPNM3

• Published in: Advanced science Vol. 9; no. 35; pp. e2204649 - n/a
• Main Authors: Liu, Zihao, Shi, Yu, Lv, Li, Chen, Jianing, Jiang, WenG, Li, Jun, Lin, Qun, Fang, Xiaolin, Gao, Jingbo, Liu, Yujie, Liu, Qiang, Xu, Xiaoding, Song, Erwei, Gong, Chang
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.12.2022; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Calcium-Binding Proteins - antagonists & inhibitors; Cancer therapies; Chemokines; CRISPR; Crystal structure; Female; Genomes; Humans; Kinases; Ligands; Medical prognosis; Membrane Proteins - antagonists & inhibitors; Metastasis; Mice; Molecular Targeted Therapy; Nanoparticle Drug Delivery System; Neoplasm Metastasis; pan‐cancer analysis; Phosphorylation; PITPNM3; Proteins; Signal Transduction; small molecular inhibitors; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Survival analysis; Xenograft Model Antitumor Assays; small molecular inhibitors; metastasis; PITPNM3; pan-cancer analysis
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202204649

Most cancer‐related deaths are a result of metastasis. The development of small molecular inhibitors reversing cancer metastasis represents a promising therapeutic opportunity for cancer patients. This pan‐cancer analysis identifies oncogenic roles of membrane‐associated phosphatidylinositol transfer protein 3 (PITPNM3), which is crucial for cancer metastasis. Small molecules targeting PITPNM3 must be explored further. Here, PITPNM3‐selective small molecular inhibitors are reported. These compounds exhibit target‐specific inhibition of PITPNM3 signaling, thereby reducing metastasis of breast cancer cells. Besides, by using nanoparticle‐based delivery systems, these PITPNM3‐selective compounds loaded nanoparticles significantly repress metastasis of breast cancer in mouse xenograft models and organoid models. Notably, the results establish an important metastatic‐promoting role for PITPNM3 and offer PITPNM3 inhibition as a therapeutic strategy in metastatic breast cancer. Pan‐cancer analysis identifies oncogenic roles of membrane‐associated phosphatidylinositol transfer protein 3 (PITPNM3). Small molecule inhibitors targeting PITPNM3 exhibit target‐specific inhibition of PITPNM3 signaling, thereby reducing metastasis of breast cancer. By using nanoparticle‐based delivery systems, PITPNM3‐selective compounds loaded nanoparticles significantly repress metastasis of breast cancer in vivo and in vitro.