Computational prediction and experimental validation of a novel synthesized pan-PIM inhibitor PI003 and its apoptosis-inducing mechanisms in cervical cancer

Oncotarget
Zhongyu LiuChunfang Gao

Abstract

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...Continue Reading

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Citations

Jan 12, 2017·Cellular Oncology (Dordrecht)·Christophe Van NesteTim De Meyer
May 13, 2017·Oncology Reports·Yong WangWei Zhao
Nov 1, 2020·Bioorganic & Medicinal Chemistry·Camilo E QuevedoAngela J Russell
May 29, 2021·Future Science OA·Deng KaiyuanZang Yunhui
Jul 3, 2021·Investigational New Drugs·Ean-Jeong SeoThomas Efferth

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Methods Mentioned

BETA
xenograft
NMR
flow cytometry
interaction predictions
protein assay
PCR

Software Mentioned

mT
SAM
Matlab
miRWalk
miRanda
DIANA
VMD
PITA
IntAct
PrePPI

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