Computational prediction and experimental validation of a novel synthesized pan-PIM inhibitor PI003 and its apoptosis-inducing mechanisms in cervical cancer.
PIM protein family, short-lived serine/threonine kinases (PIM1, PIM2 and PIM3), are weak oncogenes but contribute to tumorigenesis as cancer targets. Thus, design of a novel pan-PIM inhibitor is still a challenge for current cancer drug discovery. Herein, we used a Naïve Bayesian model to construct the PIM network and identified Bad and Hsp90 to interact with PIMs. Then, we screened a series of candidate small-molecule compounds targeting PIMs, and subsequently synthesized a novel small-molecule compound PI003 with remarkable anti-proliferative activities in cervical cancer cells. Moreover, we found that PI003 induced apoptosis via the death-receptor and mitochondrial pathways by targeting PIMs and affecting Bad and Hsp90. Combined with microRNA microarray analyses, we demonstrated that some microRNAs such as miR-1296 and miR-1299 could affect PIM1-STAT3 pathway in PI003-induced apoptosis. Finally, we reported that PI003 had remarkable anti-tumor activity and apoptosis-inducing effect in in vivo mouse model. In conclusion, these results demonstrate that PI003, as a novel synthesized pan-PIM inhibitor, induces the death-receptor and mitochondrial apoptosis involved in microRNA regulation, and also possessed remarkable anti-tumor activity and apoptosis-inducing effect in vivo. Thus, these findings would shed light on discovering more potential new small-molecule pan-PIM inhibitors in future cervical cancer therapy.
Anal-Colorectal Surgery Institute, No.150 Central Hospital of PLA, Luoyang, Henan 471031, China.
Zhongyu
Z
Liu
Anal-Colorectal Surgery Institute, No.150 Central Hospital of PLA, Luoyang, Henan 471031, China.
Weihua
W
He
Anal-Colorectal Surgery Institute, No.150 Central Hospital of PLA, Luoyang, Henan 471031, China.
Jianglin
J
Gao
Department of Obstetrics & Gynecology, No.150 Central Hospital of PLA, Luoyang, Henan 471031, China.
Junhua
J
Luo
Anal-Colorectal Surgery Institute, No.150 Central Hospital of PLA, Luoyang, Henan 471031, China.
Xian
X
Huang
Anal-Colorectal Surgery Institute, No.150 Central Hospital of PLA, Luoyang, Henan 471031, China.
Chunfang
C
Gao
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001499:Bayes Theorem; D045744:Cell Line, Tumor; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D051573:Proto-Oncogene Proteins c-pim-1
HeLa cell; PIM kinase family; apoptosis; microRNA; pan-PIM inhibitor (PI003)