Related Experiment Videos

Repurposing simeprevir uncovers a druggable KPNB1-p65-BCL2 survival axis in cancer

Cong Li1, Qiaohua Yan2, Muhammad Muddasar Saeed3

  • 1Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, Collaborative Innovation Centre of Biotherapy, Chengdu, Sichuan 610041, China.

Cell Chemical Biology
|July 31, 2026
PubMed

Insights

Cancer cells hijack nuclear import receptor KPNB1 (importin β1) for survival. New inhibitors, simeprevir and lusutrombopag, block KPNB1, suppressing cancer growth by targeting the KPNB1-p65-Bcl-2 axis.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Drug Discovery

Background:

  • Proper protein localization is crucial for cell function, but cancer cells manipulate this process.
  • KPNB1 (importin β1) is overexpressed in cancers, yet its role in oncogenesis and therapeutic potential are not fully understood.

Purpose of the Study:

  • To identify KPNB1 inhibitors and elucidate the KPNB1-mediated survival mechanisms in cancer.
  • To evaluate the therapeutic potential of identified KPNB1 inhibitors.

Main Methods:

  • Screening of an FDA-approved compound library to identify KPNB1 inhibitors.
  • Assessing the impact of inhibitors on KPNB1-mediated nuclear import, gene transcription, and apoptosis.
  • In vivo studies using xenografts and analysis of The Cancer Genome Atlas (TCGA) datasets.

Main Results:

  • Simeprevir (Sim) and lusutrombopag (Lus) were identified as direct KPNB1 inhibitors disrupting import complex assembly.
  • Sim and Lus blocked p65 nuclear import, suppressed Bcl-2 transcription, and induced mitochondrial apoptosis.
  • Sim demonstrated efficacy in suppressing tumor growth in A549 xenografts with no observable toxicity and validated the KPNB1-p65-Bcl-2 axis in TCGA data.

Conclusions:

  • A therapeutically targetable KPNB1-p65-Bcl-2 survival axis in multiple cancers was elucidated.
  • Simeprevir and lusutrombopag show promise as novel cancer therapeutics targeting KPNB1.
  • This study provides a foundation for developing next-generation KPNB1 inhibitors for cancer treatment.
Keywords:
Bcl-2KPNB1drug repurposingnuclear importp65/NF-κBsimeprevir

Related Concept Videos

Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...